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The launch of the MDUK Oxford Neuromuscular Centre marks an exciting new stage in the partnership between Muscular Dystrophy UK and the University of Oxford, with the goal of delivering new experimental medicines and developing enhanced clinical trial capacity in adult and paediatric neuromuscular diseases.
Simulated kangaroo care in very preterm infants does not reduce physiological instability: the COSYBABY randomised controlled cross-over trial.
INTRODUCTION: Infants who are born very preterm experience frequent episodes of physiological instability including apnoea, oxygen desaturation and bradycardia due to immaturity of the pulmonary and nervous systems. Parental contact, such as kangaroo care, may reduce physiological instability. However, there may be long periods when parents cannot be with their baby. The BABYBE SYSTEM® is a medical device designed to simulate kangaroo care. METHODS: We conducted a randomised cross-over trial to determine whether episodes of apnoea and other episodes of physiological instability were reduced when infants were on an active BABYBE mattress. Each infant was included in the study for five consecutive days, with successive 12-h periods of the BABYBE® mattress being switched on or off. Episodes of physiological instability were identified from recordings of the vital signs monitors and compared with clinical notes. Generalised estimating equations models were used to compare physiological instability when the BABYBE mattress was switched on vs. off. RESULTS: A total of 23 infants born before 32 weeks' gestation were included in the main analysis. There was no significant difference between the number of apnoeic episodes infants experienced in the 12-h period when the BABYBE mattress was on compared with when the mattress was switched off (difference between conditions = 1.5 apnoeas, 95% CI: -0.2-3.2, p = 0.09). The number of episodes of apnoea identified from vital signs recordings were much higher than those documented in the clinical records (a total of 1,157 apnoeic episodes were identified across all infants from vital signs recordings compared with a total of 27 documented in clinical/nursing notes of the same infants). DISCUSSION: This trial does not provide evidence of a benefit of the BABYBE mattress for improving physiological stability in preterm infants. This study provides confirmation of the under-recognition of apnoeic episodes in clinical notes and the benefit of assessing electronic recordings of vital signs to gain a more complete picture of physiological stability.
Early mucosal responses following a randomised controlled human inhaled infection with attenuated Mycobacterium bovis BCG.
The development of an effective vaccine against Mycobacterium tuberculosis is hampered by an incomplete understanding of immunoprotective mechanisms. We utilise an aerosol human challenge model using attenuated Mycobacterium bovis BCG, in BCG-naïve UK adults. The primary endpoint of this study (NCT03912207) was to characterise the early immune responses induced by aerosol BCG infection, the secondary endpoint was to identify immune markers associated with in-vitro protection. Blinded volunteers were randomised to inhale 1 × 107 CFU aerosolised BCG or 0.9% saline (20:6); and sequentially allocated to bronchoscopy at day 2 or 7 post-inhalation (10 BCG, 3 saline each timepoint). In the bronchoalveolar lavage post-aerosol BCG infection, there was an increase in frequency of eosinophils, neutrophils, NK cells and Donor-Unrestricted T cells at day 7, and the frequency of antigen presenting cells decreased at day 7 compared with day 2. The frequency of interferon-gamma+ BCG-specific CD4+ T cells increased in the BAL and peaked in the blood at day 7 post-BCG infection compared to day 2. BAL cells at day 2 and day 7 upregulated gene pathways related to phagocytosis, MHC-II antigen loading, T cell activation and proliferation. BCG's lack of key virulence factors and its failure to induce granulomas, may mean the observed immune responses do not fully recapitulate Mycobacterium tuberculosis infection. However, human infection models can provide unique insights into early immune mechanisms, informing vaccine design for complex pathogens.
Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
Abstract Chromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q (‘chr. 21amp’) in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
Patient and caregiver spinal muscular atrophy treatment attribute preferences in Latin America.
BACKGROUND: Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease associated with a significant burden of illness to both patients and caregivers; however, there is little evidence available regarding how patients and caregivers evaluate potential treatment benefit-risk profiles. As access to SMA disease-modifying therapies increases, it is imperative to understand which treatment attributes drive treatment choices. OBJECTIVE: To identify which treatment attributes drive treatment choices in adults with SMA and caregivers of children with SMA across nine countries in Latin America. METHODS: A discrete choice experiment (DCE) survey was developed for market research using data collected via qualitative interviews and consultations with medical experts. Adults with Type 2/3 SMA and caregivers of children with Types 1-3 SMA were recruited by patient advisory groups and physician referrals. Respondents completed a 30-min, online survey that collected patient demographics, disease-specific information, and quality of life data (via the EQ-5D-5L), and included the DCE, in which respondents were asked to choose between 14 sets of hypothetical treatment profiles. Data were pooled for analysis, as the country-level sample sizes were small. Raw data were aggregated in Microsoft Excel. Statistical testing was performed using data tables and SPSS (as appropriate). Demographic data were summarized descriptively. RESULTS: A total of 143 respondents (45 adults with SMA and 98 caregivers) completed the online survey. Most respondents were from Argentina (35.0%) or Brazil (19.6%). Breathing function outcome was the most important treatment attribute for caregivers, while adults with SMA placed greater importance on motor function outcome. Both adults with SMA and caregivers placed the greatest importance on improvements in function compared with worse or stable outcomes. CONCLUSIONS: Understanding treatment attribute preferences at a regional level will improve shared medical decision-making for individuals with SMA.
A systematic review on motor outcome measures in congenital myopathy.
Congenital myopathies (CMYOs) encompass a group of genetically heterogeneous rare muscle disorders with clinical features including hypotonia, muscle weakness leading to delayed or absent motor milestones, feeding and respiratory difficulties, and a myopathic facial appearance. CMYO categorisation includes: Nemaline Myopathy, Core Myopathy, Central Core Disease, Multi-Mini Core Disease, Congenital Fiber-type Disproportion Myopathy, Myosin Storage Myopathy, Centronuclear Myopathy, Myotubular Myopathy, X-linked Myotubular Myopathy, and Autosomal Centronuclear Myopathy. The aim of this systematic review is to evaluate the current evidence base of motor outcome measures used in the assessment of CMYO. Methodology was in accordance with the PRISMA 2020 guidelines and registered (PROSPERO CRD42024569701). Databases searched include PubMed, EMBASE, and Cochrane library. Peer reviewed, full-text, English language publications were included. The 31 articles included motor outcome measures of motor function, gross motor, muscle strength, and endurance. Twenty-six motor outcome measures were identified and all were found to have limited disease-specific metrics. This systematic review discussed motor outcome measure suitably in relation to disease characteristics and identified the lack of disease-specificity as the largest gap for future research.
Data-driven consideration of genetic disorders for global genomic newborn screening programs.
PURPOSE: Over 30 international studies are exploring newborn sequencing (NBSeq) to expand the range of genetic disorders included in newborn screening. Substantial variability in gene selection across programs exists, highlighting the need for a systematic approach to prioritize genes. METHODS: We assembled a data set comprising 25 characteristics about each of the 4390 genes included in 27 NBSeq programs. We used regression analysis to identify several predictors of inclusion and developed a machine learning model to rank genes for public health consideration. RESULTS: Among 27 NBSeq programs, the number of genes analyzed ranged from 134 to 4299, with only 74 (1.7%) genes included by over 80% of programs. The most significant associations with gene inclusion across programs were presence on the US Recommended Uniform Screening Panel (inclusion increase of 74.7%, CI: 71.0%-78.4%), robust evidence on the natural history (29.5%, CI: 24.6%-34.4%), and treatment efficacy (17.0%, CI: 12.3%-21.7%) of the associated genetic disease. A boosted trees machine learning model using 13 predictors achieved high accuracy in predicting gene inclusion across programs (area under the curve = 0.915, R2 = 84%). CONCLUSION: The machine learning model developed here provides a ranked list of genes that can adapt to emerging evidence and regional needs, enabling more consistent and informed gene selection in NBSeq initiatives.
Inflammatory disease microbiomes share a functional pathogenicity predicted by C-reactive protein.
We examine disease-specific and cross-disease functions of the human gut microbiome by colonizing germ-free mice, at risk for inflammatory arthritis, colitis, or neuroinflammation, with over 100 human fecal microbiomes from subjects with rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, ulcerative colitis, Crohn's disease, or colorectal cancer. We find common inflammatory phenotypes driven by microbiomes from individuals with intestinal inflammation or inflammatory arthritis, as well as distinct functions specific to microbiomes from multiple sclerosis patients. Inflammatory disease in mice colonized with human microbiomes correlated with systemic inflammation, measured by C-reactive protein, in the human donors. These cross-disease patterns of human microbiome pathogenicity mirror features of the inflammatory diseases, including therapeutic targets and the presence or absence of systemic inflammation, suggesting shared and disease-specific mechanisms by which the microbiome is shaped and drives pathogenic inflammatory responses.
Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes.
Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis.
C5a and C5aR are elevated in joints of rheumatoid and psoriatic arthritis patients, and C5aR blockade attenuates leukocyte migration to synovial fluid.
Complement activation correlates to rheumatoid arthritis disease activity, and increased amounts of the complement split product C5a is observed in synovial fluids from rheumatoid arthritis patients. Blockade of C5a or its receptor (C5aR) is efficacious in several arthritis models. The aim of this study was to investigate the role of C5a and C5aR in human rheumatoid arthritis and psoriatic arthritis-both with respect to expression and function. Synovial fluid, blood and synovial samples were obtained from rheumatoid arthritis, psoriatic arthritis and osteoarthritis patients as a less inflammatory arthritis type, and blood from healthy subjects. Cells infiltrating synovial tissue were analysed by immunohistochemistry and flow cytometry. SF and blood were analysed for biomarkers by flow cytometry or ELISA. The effect of a blocking anti-human C5aR mAb on leukocyte migration was determined using a Boyden chamber. Appropriate statistical tests were applied for comparisons. C5aR+ cells were detected in most rheumatoid arthritis, in all psoriatic arthritis, but not in non-inflammatory control synovia. C5aR+ cells were primarily neutrophils and macrophages. C5aR+ macrophages were mainly found in lymphoid aggregates in close contact with T cells. C5a levels were increased in both rheumatoid arthritis and psoriatic arthritis synovial fluid compared to osteoarthritis, and in blood from rheumatoid arthritis compared to healthy subjects. Neutrophil and monocyte migration to rheumatoid arthritis synovial fluid was significantly inhibited by anti-C5aR. The data support that the C5a-C5aR axis may be driving the infiltration of inflammatory cells into the synovial fluid and synovium in both rheumatoid and psoriatic arthritis, and suggest that C5a or C5aR may be a promising treatment target in both diseases.
Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis.
Osteoclasts are bone-eroding cells that develop from monocytic precursor cells in the presence of receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Osteoclasts are essential for physiological bone remodeling, but localized excessive osteoclast activity is responsible for the periarticular bone destruction that characteristically occurs in patients with rheumatoid arthritis (RA). The origin of osteoclasts at sites of bone erosion in RA is unknown. Natural killer (NK) cells, as well as monocytes, are abundant in the inflamed joints of patients with RA. We show here that such NK cells express both RANKL and M-CSF and are frequently associated with CD14(+) monocytes in the RA synovium. Moreover, when synovial NK cells are cocultured with monocytes in vitro, they trigger their differentiation into osteoclasts, a process dependent on RANKL and M-CSF. As in RA, NK cells in the joints of mice with collagen-induced arthritis (CIA) express RANKL. Depletion of NK cells from mice before the induction of CIA reduces the severity of subsequent arthritis and almost completely prevents bone erosion. These results suggest that NK cells may play an important role in the destruction of bone associated with inflammatory arthritis.
Natural killer cells trigger differentiation of monocytes into dendritic cells.
Circulating monocytes can differentiate into dendritic cells (moDCs), which are potent inducers of adaptive immune responses. Previous reports show that granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 induce monocyte differentiation into moDCs in vitro, but little is known about the physiological requirements that initiate moDC differentiation in vivo. Here we show that a unique natural killer (NK) cell subset (CD3(-)CD56(bright)) that accumulates in lymph nodes and chronically inflamed tissues triggers CD14(+) monocytes to differentiate into potent T-helper-1 (T(H)1) promoting DC. This process requires direct contact of monocytes with NK cells and is mediated by GM-CSF and CD154 derived from NK cells. It is noteworthy that synovial fluid (SF) from patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), but not osteoarthritis (OA), induces monocytes to differentiate into DC. However, this process occurs only in the presence of NK cells. We propose that NK cells play a role in the maintenance of T(H)1-mediated inflammatory diseases such as RA by providing a local milieu for monocytes to differentiate into DC.
Translational science at the undergraduate level: awakening talents to overcome the valley of death - case report.
BACKGROUND: In the biomedical field, translational science is the process of applying basic scientific knowledge to advance clinical research through the creation of new drugs, devices, medical procedures, preventive measures, and diagnostic kits. The Covid-19 pandemic exposed a shortage of professionals trained in translational research, essential for responding to global demands. To drive advancements, researchers must overcome the 'valley of death', a critical phase in clinical investigation. In response, CEVAP at São Paulo State University (UNESP), Botucatu, Brazil, has developed a strong 'knowledge industry' centered on Translational Science. As part of its research and innovation efforts, CEVAP has developed two biopharmaceuticals, the fibrin sealant and the apilic antivenom, which are currently in the final stage of development. In 2024, CEVAP began the first Brazilian Contract Development and Manufacturing Organization (CDMO) for developing and producing validated and qualified pilot-scale batches to generate clinical trial material. CASE PRESENTATION: The implementation of the optional undergraduate course in Translational Science marks a crucial step in strengthening the 'knowledge industry'. The program, developed in collaboration with São Paulo's three public universities (USP, UNESP, and UNICAMP), also involves an international partnership with the University of Oxford's Department of Pediatrics and the Oxford Research Group LATAM. The successful launch of this course underscores its importance in interdisciplinary education and institutional collaboration. By bridging gaps between research and application, the program equips professionals to meet the growing demand for expertise in translational science. Given the project's success, it will transition into a one-year 'Qualification in Translational Science', available to students enrolled in São Paulo state universities. CONCLUSION: The preparation of these professionals will be strategic for transforming basic research into products for health, saving lives, and combating future pandemics that will emerge around the world.
TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.
Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b-/- mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.
Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells.
The network of thymic stromal cells provides essential niches with unique molecular cues controlling T cell development and selection. Recent single-cell RNA sequencing studies have uncovered previously unappreciated transcriptional heterogeneity among thymic epithelial cells (TEC). However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here, using massively parallel flow cytometry and machine learning, we deconvoluted known TEC phenotypes into novel subpopulations. Using CITEseq, these phenotypes were related to corresponding TEC subtypes defined by the cells' RNA profiles. This approach allowed the phenotypic identification of perinatal cTEC and their physical localisation within the cortical stromal scaffold. In addition, we demonstrate the dynamic change in the frequency of perinatal cTEC in response to developing thymocytes and reveal their exceptional efficiency in positive selection. Collectively, our study identifies markers that allow for an unprecedented dissection of the thymus stromal complexity, as well as physical isolation of TEC populations and assignment of specific functions to individual TEC subtypes.
CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue.
OBJECTIVES: Interleukin (IL)-17A is a key driver of spondyloarthritis (SpA) joint pathology. We aimed to identify its cellular source in synovial tissue from patients with 2 forms of SpA, namely axial SpA (AxSpA) and psoriatic arthritis (PsA). METHODS: Synovial tissue from patients with SpA was profiled using single-cell RNA sequencing (scRNA-seq; AxSpA, n = 5; PsA, n = 6) or spatial RNA profiling (PsA, n = 4). CellPhoneDB was used to infer cell-cell communication. Tissue-resident memory Th17 (TRM17)-like cells were generated in vitro using blood memory CD4+ T cells from SpA patients. An epigenetic inhibitor library, siRNA, and clustered regularly interspaced short palindromic repeats (CRISPR) were used to identify epigenetic regulator(s) for TRM17. RESULTS: scRNA-seq showed that CD4+CXCR6+ TRM17 cells are the predominant spontaneous IL17A producers in SpA synovium. Cell-cell communication and single-cell spatial analysis support the interaction between TRM17 and CLEC10A+ dendritic cells, which were activated in SpA. Both sublining and lining fibroblasts in SpA synovium showed evidence of interleukin (IL)-17A activation. In vitro-generated CD4+ TRM17-like cells phenocopied joint tissue TRM17, producing IL-17A/F upon T cell-receptor (TCR) stimulation, which was further enhanced by cytokines. Perturbation of BRD1 inhibited the generation of TRM17-like cells. CONCLUSIONS: CD4+ TRM17 cells are the predominant source of IL-17A in SpA synovial tissue. TCR stimulation is essential for the secretion of IL-17A by CD4+TRM17-like cells. The epigenetic regulator bromodomain-containing protein 1 (BRD1) contributes to the generation of CD4+TRM17. Depleting CD4+TRM17 cells in SpA is thus a therapeutic strategy with potential to induce long-term remission.
Predicting expression-altering promoter mutations with deep learning.
Only a minority of patients with rare genetic diseases are currently diagnosed by exome sequencing, suggesting that additional unrecognized pathogenic variants may reside in non-coding sequence. Here, we describe PromoterAI, a deep neural network that accurately identifies non-coding promoter variants which dysregulate gene expression. We show that promoter variants with predicted expression-altering consequences produce outlier expression at both RNA and protein levels in thousands of individuals, and that these variants experience strong negative selection in human populations. We observe that clinically relevant genes in rare disease patients are enriched for such variants and validate their functional impact through reporter assays. Our estimates suggest that promoter variation accounts for 6% of the genetic burden associated with rare diseases.
Pain in women: bridging the gender pain gap.
Bridging the gender pain gap requires collaborative efforts that address female-specific biological and psychosocial dimensions of pain through evidence-based, compassionate and empathy-driven approaches.