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5. The transcriptional regulation of the zeta-globin gene

Author

Liu, Siyu, Roy, A, Palis, J, Higgs, D, Babbs, C, and Gibbons, R

Abstract

The ζ-globin gene (HBZ in humans and Hba-x in mice) is the embryonic α-like globin gene that is expressed at the early stages of primitive erythropoiesis but silenced in the definitive erythroid lineage. Understanding the regulation of ζ-globin transcription, especially the mechanisms by which it is silenced, would shed light on gene regulation and offer therapeutic opportunities for ζ-globin induction in patients with severe α-thalassemia. Previous studies in the laboratory have excluded many common mechanisms of gene silencing, here, Polycomb repression mediated by PRC1 has also been excluded as a participant in ζ-globin silencing. Of interest, histone deacetylation mediated via the NuRD complex appears to play a role in ζ-globin silencing in definitive erythropoiesis. However, the constantly hypoacetylated ζ-globin locus shows no enrichment of NuRD complex in definitive erythroblasts by ChIP-seq, suggesting the potential role of NuRD in ζ-globin silencing may rely on its nucleosome remodelling activity rather than its histone deacetylase components. In contrast to the definitive erythroid lineage, ζ-globin repression is independent of histone deacetylation during the primitive intra-lineage switch. A comprehensive CRISPR screen across the ζ-globin promoter has identified two repressive cis-acting elements, which are predicted binding motifs of LRF and BCL11A; two transcription factors known to be responsible for ζ-globin repression. Perturbation of the LRF motif has a greater effect than altering the BCL11A motif in definitive erythroblasts from mice and humans. Base editing of both elements increases ζ-globin to 20% of total α-like globin transcription and a pan-cellular ζ-globin induction at the protein level. This effect size is similar to that seen in the LRF and BCL11A double knockout model, showing that these two factors repress ζ-globin transcription by direct promoter binding. It has previously been shown that individuals with a common deletion of the α-globin genes, termed Southeast Asian deletion (--SEA), which leaves the embryonic ζ-gene intact, have a raised level of ζ-globin expression. To gain insight into the mechanisms of ζ-globin gene expression in such cases, a mouse model that recapitulates the --SEA mutation in humans has been generated and characterised. This model has shown that promoter competition within the α-globin cluster plays an important part in ζ-globin silencing during the primitive intra-lineage switch, suggesting that in the definitive erythroid lineage, in addition to trans-acting factors, promoter competition may also play a role in determining the level of ζ-globin reactivation.

Published
2023
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6. The role of chromatin remodeller ATRX in gene expression

Author

Shen, Y, Milne, T, Picketts, D, Gibbons, R, and Higgs, D

Subjects
Human molecular genetics, Medical sciences
Abstract

ATRX is a chromatin remodeller involved in a wide range of nuclear processes, including transcription. Germline mutations in ATRX give rise to alpha- thalassaemia/intellectual disability X-linked (ATR-X) syndrome and downregulate alpha globin expression through a mechanism which is poorly understood. To understand how ATRX regulates gene expression, here I use alpha thalassaemia as an exemplar to study how ATRX loss downregulates alpha globin expression, which would provide insights into understanding the general gene regulation mechanism of ATRX. Specifically, I aim to recapitulate the alpha thalassaemia phenotype observed in ATR-X syndrome patients in an ATRX deficient erythroid cell system, and then to determine the molecular mechanisms that cause perturbed alpha globin expression. To this end, an ATRX deficient CD34+ haematopoietic stem cell model was generated via CRISPR-Cas9. However, the cells did not show distinct alpha thalassaemia phenotype at the bulk level when differentiated into erythrocytes. Further gene expression analysis in single erythroid colony and single erythroid cell RNA-seq revealed that ATRX deficiency led to alpha thalassaemia in only a subset of cells. Differential gene expression analysis indicated the downregulation of alpha-like globin was likely associated with replicative stress/DNA damage, in particular the activated pATM-RNF168-ubiquitination pathway. To validate the mechanisms, an erythroid progenitor cell line containing a dTAG-13 inducible ATRX degron system was generated, in which the alpha-like globin gene was tagged with a fluorescent reporter for the enrichment of the affected cell subpopulation. This cell model recapitulated the alpha thalassaemia phenotype and was used to investigate the function and gene regulation mechanism of ATRX. It has been shown that ATRX mainly regulates alpha globin expression at the basophilic erythroblast stage, and ATRX loss-induced alpha globin downregulation is not associated with DNA methylation. As a prime candidate for causing replicative stress/DNA damage in the absence of ATRX, a putative G4 DNA-forming region ψζ VNTR in the alpha globin cluster was studied to explore its contribution to the gene regulation. It is demonstrated that ATRX binds to this region in a gene expression dependent manner. G4 stabilizer treatment downregulated α-globin gene expression and deletion of this region in erythroid cells abolished the effect of ATRX depletion on alpha globin expression, indicating ATRX regulates alpha globin expression through binding to the G-rich ψζ VNTR.

Published
2023

7. Characterising the cellular and molecular basis of age-related clonal haematopoiesis

Author

Jakobsen, NA, Vyas, P, and Higgs, D

Subjects
Aging, Molecular biology, Hematology
Abstract

Throughout life, tissue stem cells accumulate somatic mutations. Occasionally, a mutation may occur that confers a selective advantage leading to growth of an expanded clone. When this occurs in haematopoietic stem cells (HSC), this is called clonal haematopoiesis. Clonal haematopoiesis is common in healthy older people, and is associated with increased risk of haematological malignancy and other adverse outcomes. Surprisingly, most cases of clonal haematopoiesis are associated with mutations in just two genes, DNMT3A and TET2, which regulate DNA methylation. Mutations in these genes are often the first genetic event in myeloid and lymphoid malignancies and may be acquired many years before the onset of disease. The mechanisms by which mutations in DNMT3A and TET2 cause clonal expansion are poorly understood and no studies have analysed their consequences in humans with unperturbed clonal haematopoiesis. This study characterises the cellular and molecular consequences of somatic DNMT3A and TET2 mutations in humans with clonal haematopoiesis. Blood and bone marrow samples were collected from a cohort of 195 individuals undergoing total hip replacement surgery. DNA sequencing identified 85 cases with clonal haematopoiesis with a similar profile of mutations to those in the general population. Most individuals had normal blood counts and bone marrow immunophenotyping showed that clonal haematopoiesis is usually associated with normal stem and progenitor frequencies. I adapted the TARGET-seq method to develop a more sensitive method for combined single cell genotyping with whole transcriptome sequencing. The new TARGET-seq+ method detected more genes per cell with lower dropout rates and reduced technical variation. I applied TARGET-seq+ to 12,847 single cells from 10 samples with clonal haematopoiesis and 3 controls. DNMT3A and TET2-mutant haematopoietic stem and progenitor cells did not occupy novel transcriptional states, but intermingled with wild-type cells, showing they follow a common differentiation trajectory. Expansion of DNMT3A-mutant clones occurred mainly in HSC and the greatest clone size was reached in early multipotent progenitors. In contrast, TET2-mutant clones expanded later in differentiation with a transcriptional bias towards the myeloid lineage. These findings highlight distinct effects of DNMT3A and TET2 mutations on haematopoietic stem and progenitor cells and identify dysregulated pathways that may have a role in expansion of the mutant clone.

Published
2023

8. Developing genome-editing strategies to ameliorate HbE/beta-thalassaemia

Author

Badat, M, Davies, B, Weiss, M, Higgs, D, Davies, J, and Gibbons, R

Abstract

The thalassaemias are the most common monogenic disorders worldwide. Both α- and β-thalassaemia are caused by genetic mutations that result in a decrease in globin gene expression and protein synthesis. The more clinically significant of the two disorders, β-thalassaemia is mainly caused by point mutations in the β-globin gene or proximal sequences. Patients develop severe anaemia early in life and are dependent on life-long blood transfusions. The relative excess free α-globin chains in developing erythroblasts causes apoptosis and necrosis, resulting in ineffective erythropoiesis and the resulting severe phenotype. Decades of careful clinical observational studies have shown that individuals with severe β-thalassaemia who co-inherit α-globin gene mutations often have a mild or asymptomatic phenotype. This is especially, but not limited to, individuals with HbE/β-thalassaemia which causes half of all severe β-thalassaemia worldwide. The α- and β-globin gene clusters are among the most finely characterised loci in the human genome, and this understanding of gene regulation in normal and pathological contexts allows the development of tailored therapeutic strategies. In this study, I have to tried to use this knowledge to develop two therapeutic strategies to cure β-thalassaemia. The first aims to tunably reduce α-globin expression by editing its main enhancer, MCS-R2, to restore globin chain balance in patients with severe β-thalassaemia. The second aims to recapitulate the asymptomatic carrier β-thalassaemia trait state by using new technology to repair the HbE mutation in-situ. Initially I aimed to further characterise the role of the main enhancer of α-globin, MCS-R2. This work was enabled through the study of a patient with severe HbH disease who had an extremely rare mutation, leaving her with two α-globin genes and a deletion of MCS-R2 on the same allele. CD34+ cells were obtained and differentiated erythroid cells were studied using various methods, including ATAC-seq and Capture-C to assess gene-expression, chromatin accessibility and architecture in the absence of the main enhancer. Next a variety of techniques were used to profile the sequence of MCS-R2 to identify key regulatory sequences that are important to its function. Several putative transcription factor binding sites were identified, and these were targeted in the development of the first therapeutic strategy. Individual binding sites were mutated using CRISPR/Cas9 with high efficiency to try and tunably reduce α-globin expression. The mutation of binding sites for canonical erythroid transcription factors resulted in the reduction of α-globin expression commensurate with a single α-globin gene deletion, which has been shown previously to be of clinical benefit in individuals with severe β-thalassaemia mutations. Next base editors, a modular variant of the CRISPR/Cas9 system, were used to repair the pathogenic codon 26 mutation in the HBB gene that causes HbE/β-thalassaemia. This system was optimised and then used in patient-derived CD34+ cells, resulting in high base-deamination efficiencies and robust production of normal β-globin protein. Serial mouse xenotransplantation experiments were performed, proving that base editing is possible in long-term repopulating haematopoietic stem cells, and the off-target landscape was assessed. In summary, through the development and utilisation of knowledge of how the main α-globin enhancer controls gene expression, and the adoption of new gene-editing technologies, this work outlines two new therapeutic strategies for curing HbE/β-thalassaemia. These have the potential to deliver significant benefit, both alone or in conjunction with gene-editing therapies currently being trialled in the clinic.

Published
2022

9. The National Joint Registry Data Quality Audit of elbow arthroplasty.

Author

Hamoodi Z, Shapiro J, Sayers A, Whitehouse MR, Watts AC, Abbott J, Abbott S, Adebayo O, Ahmad K, Ahrens P, Akinfala M, Al-Hadithy N, Al-Najjar M, Amirfeyz R, Ankarath S, Ashton F, Aulton K, Auplish S, Austin J, Ayeko S, Azhar R, Bahia R, Baines S, Baldomir M, Barai S, Barkham B, Barrett E, Batten T, Bavan L, Baxter J, Beaumont S, Bentley J, Bhabra G, Bhat M, Bhatt A, Bhingraj M, Bhutta A, Bingham S, Blastland J, Boardman D, Boateng M, Bojarska K, Boksh K, Booker S, Borreshi S, Bould M, Boulton L, Brannan L, Breidaka Z, Brereton R, Brinsden M, Brooker J, Brookes S, Broux C, Brown E, Browne J, Bryant R, Buchanan J, Buck L, Burnett K, Burrows M, Burt J, Burton D, Butt U, Campaner B, Candal-Couto J, Carvell H, Chakravarthy J, Chatterji S, Chaudhury S, Chauhan GS, Chojnowski A, Cittambalam J, Clark D, Gosia Clarke M, Clarke B, Clelland A, Cochrane R, Colbridge K, Cook H, Cooper B, Correa E, Craven J, Crawford J, Curtis S, Cuthbert R, Dainton J, Dale L, Davies S, Davis J, Davis V, Dean B, Dehler T, Dennis S, Der Tavitian J, Desai A, Dhillon SS, Dias R, Dickinson G, Dirckx M, Dixon O, Docker C, Dodenhoff R, Domos P, Draviaraj K, Drew S, Duff C, Duffin S, Durham P, Earnshaw K, Edakalathur J, Edwards M, Elahi Z, Else S, Emara M, Eng K, Esfandiari A, Esler C, Evans J, Everall A, Eyre-Brook A, Farhan-Alanie M, Federer S, Ferdinandus S, Finch M, Fischer J, Flood C, Forde C, Forder J, Fowler L, Franklin M, Gacaferi H, Gamble D, Garg S, Gill V, Ginley J, Glancey E, Glanville G, Gmati A, Goddard K, Goel J, Goldsmith C, Gooding B, Goodwin F, Goring B, Goude W, Guyver P, Haines S, Haque A, Hardley T, Haritonow S, Harnett L, Harris J, Harris M, Harrison J, Hauffe I, Hawken A, Hawkes D, Hay S, Haywood M, Hedge S, Hickey S, Hickinson A, Higgs D, Hill R, Hill S, Hind J, Hitchcock M, Holdcroft T, Holdcroft E, Holliday A, Hudson S, Hughes H, Imtiaz R, Iqbal S, Jabr Y, Jackson C, Jameson J, Jayme O, Jennings A, Jenvey C, Jewitt E, Jimenez A, Joby J, Jones A, Jones N, Jovanovic J, Kabala V, Kang N, Kausor G, Kaynes S, Keane C, Keen L, Kelly G, Kent M, Kent J, Kerr C, Kerr J, King C, Kinnair A, Kinsley G, Konarski A, Kord J, Kumar H, Kumar S, Lafferty R, Lancaster P, Levitt W, Lewin A, Li Y, Liew I, Yizhe Lim M, Lipscombe S, Lynch E, MacInnes S, Madden P, Maddocks N, Mahajan R, Mahoney R, Malik S, Mannan S, Maris A, Markey M, Martin C, Martin R, Masunda S, Mazis G, Mcauliffe AM, McBride T, McGowan A, Mckeown N, McLauchlan G, McNally D, Melton J, Miller J, Millyard C, Mitchell C, Mohamed F, Mohamed A, Charlotte Montgomery H, Munn D, Mutimer J, Nanda R, Neen D, Newton L, Newton A, Nicholl A, Nightingale J, Ogden E, Orton P, Oswald L, Page K, Paius M, Papanna M, Patel N, Paul C, Peach C, Pegg D, Penfold S, Phillips E, Pickering G, Plakogiannis C, Platt J, Pole C, Potter R, Povall K, Pradhan R, Prasad G, Price K, Pride J, Prins A, Qazzaz L, Radhakrishnan A, Ramesh A, Rashid A, Rashid A, Rasidovic D, Ratford E, Rayner J, Rhee J, Rice-Evans M, Ricketts M, Roach D, Waters ER, Robinson S, Robinson P, Rodgers S, Rogers E, Rooney A, Rossouw D, Roy B, Sadiqi M, Sagmeister M, Samy D, Sanders P, Sanderson K, Sandher D, Sargazi N, Saunders M, Saunders N, Savage K, Sawalha S, Schouw M, Scott G, Selzer G, Sepesiova L, Shah S, Shahane S, Shaw G, Shrestha S, Shutt J, Siddiqui N, Sidharthan S, Simons A, Simpson V, Sinclair P, Siney P, Singh J, Singh B, Singh H, Sinha A, Smith C, Smith C, Smith K, Somanchi B, Soufan M, Southgate C, Southgate J, Spearpoint N, Stainer R, Stevens R, Stimler B, Stone A, Suter D, Talbot C, Tareef T, Theivendran K, Thomas B, Thomas W, Thompson A, Thompson J, Thornhill E, Titchener A, Townley M, Tozer T, Truman J, Truss A, Turner R, Van Rensburg L, Venugopal V, Vollans S, Waller L, Walsh A, Waraich A, Wei N, James White W, Wilkinson M, Williams D, Williams P, Williams N, Wilson S, Wood D, Yadu S, Yarashi T, Zeolla J, Zreik NH, and Ollivere B

Subjects
Humans, Medical Audit, England, Registries, Data Accuracy, Arthroplasty, Replacement, Elbow standards, Arthroplasty, Replacement, Elbow statistics & numerical data, Elbow Joint surgery
Abstract

Aims: The aim of this audit was to assess and improve the completeness and accuracy of the National Joint Registry (NJR) dataset for arthroplasty of the elbow., Methods: It was performed in two phases. In Phase 1, the completeness was assessed by comparing the NJR elbow dataset with the NHS England Hospital Episode Statistics (HES) data between April 2012 and April 2020. In order to assess the accuracy of the data, the components of each arthroplasty recorded in the NJR were compared to the type of arthroplasty which was recorded. In Phase 2, a national collaborative audit was undertaken to evaluate the reasons for unmatched data, add missing arthroplasties, and evaluate the reasons for the recording of inaccurate arthroplasties and correct them., Results: Phase 1 identified 5,539 arthroplasties in HES which did not match an arthroplasty on the NJR, and 448 inaccurate arthroplasties from 254 hospitals. Most mismatched procedures (3,960 procedures; 71%) were radial head arthroplasties (RHAs). In Phase 2, 142 NHS hospitals with 3,640 (66%) mismatched and 314 (69%) inaccurate arthroplasties volunteered to assess their records. A large proportion of the unmatched data (3,000 arthroplasties; 82%) were confirmed as being missing from the NJR. The overall rate of completeness of the NJR elbow dataset improved from 63% to 83% following phase 2, and the completeness of total elbow arthroplasty data improved to 93%. Missing RHAs had the biggest impact on the overall completeness, but through the audit the number of RHAs in the NJR nearly doubled and completeness increased from 35% to 70%. The accuracy of data was 94% and improved to 98% after correcting 212 of the 448 inaccurately recorded arthroplasties., Conclusion: The rate of completeness of the NJR total elbow arthroplasty dataset is currently 93% and the accuracy is 98%. This audit identified challenges of data capture with regard to RHAs. Collaboration with a trauma and orthopaedic trainees through the British Orthopaedic Trainee Association improved the completeness and accuracy of the NJR elbow dataset, which will improve the validity of the reports and of the associated research., Competing Interests: Z. Hamoodi reports research fellowship funding from Royal College of Surgeons, National Joint Registry, and The John Charnley Trust, related to this study. A. Sayers is senior statistician on the HQIP/NJR Lot 2 contract. M. R. Whitehouse is the principal investigator for the HQIP/NJR Lot 2 contract to provide statistical support, analysis and associated services to the NJR, related to this study, and reports multiple grants or contracts from the NIHR and Ceramtec, royalties or licenses from Taylor & Frances, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Heraeus, all of which are unrelated to this study. A. C. Watts reports royalties or licenses and patents planned, issued or pendingfrom Adler, consulting fees from Medartis, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Medartis, Stryker, and Arthrex, all of which are unrelated to this study, and is also a member of the editorial boards of the National Joint Registry and The Bone & Joint Journal., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Published
2024
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10. Core Outcome Domains for Elbow Replacement (CODER).

Author

Watts AC, McDaid C, Hewitt C, Bateman M, Evans JP, Higgs D, Hughes B, Luokkala T, Smith C, and Uppal E

Subjects
Humans, Activities of Daily Living, Quality of Life, Elbow Joint surgery, Treatment Outcome, Outcome Assessment, Health Care, Recovery of Function, Arthroplasty, Replacement, Elbow, Delphi Technique, Patient Satisfaction
Abstract

Aims: A review of the literature on elbow replacement found no consistency in the clinical outcome measures which are used to assess the effectiveness of interventions. The aim of this study was to define core outcome domains for elbow replacement., Methods: A real-time Delphi survey was conducted over four weeks using outcomes from a scoping review of 362 studies on elbow replacement published between January 1990 and February 2021. A total of 583 outcome descriptors were rationalized to 139 unique outcomes. The survey consisted of 139 outcomes divided into 18 domains. The readability and clarity of the survey was determined by an advisory group including a patient representative. Participants were able to view aggregated responses from other participants in real time and to revisit their responses as many times as they wished during the study period. Participants were able to propose additional items for inclusion. A Patient and Public Inclusion and Engagement (PPIE) panel considered the consensus findings., Results: A total of 45 respondents completed the survey. Nine core mandatory domains were identified: 'return to work or normal daily role'; delivery of care was measured in the domains 'patient satisfaction with the outcome of surgery' and 'would the patient have the same operation again'; 'pain'; 'revision'; 'elbow function'; 'independence in activities of daily living'; 'health-related quality of life'; and 'adverse events'. 'Elbow range of motion' was identified as important by consensus but was felt to be less relevant by the PPIE panel. The PPIE panel unanimously stated that pain should be used as the primary outcome domain., Conclusion: This study defined core domains for the clinical outcomes of elbow replacement obtained by consensus from patients, carers, and healthcare professionals. Pain may be used as the primary outcome in future studies, where appropriate. Further work is required to define the instruments that should be used., Competing Interests: A. C. Watts reports grants or contracts from NIHR, Zimmer Biomet, TRB Chemedica, and Stryker, royalties or licenses and patents planned, issued or pending from Adler, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Xiros, Medartis, and Arthrex, all of which are unrelated to this study. C. McDaid reports grants or contracts from NIHR HTA and i4i panels, research funding from Hull Teaching Hospitals NHS Trust, and is the co-director of NIHR RSS, all of which are unrelated to this study., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Published
2024
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11. Developing a pill to treat sickle cell disease.

Author

Higgs D and Kassouf M

Subjects
Animals, Humans, Mice, Drug Discovery, Anemia, Sickle Cell drug therapy, Epigenesis, Genetic drug effects, Fetal Hemoglobin genetics, Antisickling Agents chemistry, Antisickling Agents pharmacology, Antisickling Agents therapeutic use
Abstract

A newly identified epigenetic modifier increases fetal hemoglobin in preclinical studies.

Published
2024
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12. Survivorship analysis of CAD-CAM total shoulder replacement.

Author

Nayar SK, Butt D, Prinja A, Rudge W, Majed A, Higgs D, and Falworth M

Abstract

Background: Glenoid bone loss represents a challenge in shoulder arthroplasty and often precludes standard implants. The CAD-CAM total shoulder replacement (TSR) is an option in these cases. This study aimed to assess survivorship and long-term patient outcomes of the CAD-CAM TSR., Methods: Fifty-eight patients that underwent a CAD-CAM TSR by three surgeons at a single tertiary referral centre between 2009 and 2017 were reviewed. The mean follow-up was 70 months (28-130). Data was collected on survivorship, range of movement, Oxford shoulder score (OSS, 0-48), subjective shoulder value (SSV, 0-100%), pain score (0-10), and overall patient satisfaction., Results: CAD-CAM TSR was undertaken as a primary procedure in 28% ( n  = 16) for end-stage arthritis with severe glenoid bone loss, and as a revision procedure in 72% ( n  = 42). Of the total, 17% ( n  = 10) required component revision at a mean of 24 months (4x prosthesis loosening, 3x infection, 3x periprosthetic fracture). Forward elevation improved from 45° ± 27° to 59° ± 29° (P = 0.0056), abduction from 43° ± 29° to 55° ± 26° (P = 0.034) and external rotation from 8° ± 11° to 16° ± 14° (P = 0.031). OSS improved from 15 ± 8 to 29 ± 9 (P = 0.0009), SSV from 18 ± 16 to 62 ± 23 (P < 0.0001), and pain score from 8 ± 2 to 2 ± 2 (P < 0.0001). 88% of patients would undergo the procedure again., Conclusion: CAD-CAM TSR is reserved for complex cases involving severe glenoid bone loss, offering significant improvements in pain and function with overall positive patient satisfaction., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Published
2024
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13. A systematic review of the treatment of distal humerus fractures in older adults: A comparison of surgical and non-surgical options.

Author

Stoddart MT, Panagopoulos GN, Craig RS, Falworth M, Butt D, Rudge W, Higgs D, and Majed A

Abstract

Background: Fractures of the distal humerus are a common fragility fracture in older adults. The purpose of this study was to systematically review the literature to produce pooled estimates of the outcomes of treatment using total elbow arthroplasty (TEA), open reduction and locking plate fixation (ORIF), hemiarthroplasty or with conservative management., Methods: A systematic review of PUBMED and EMBASE databases was conducted for studies reporting outcomes of intra-articular fractures in older adults. Data extracted included patient-reported outcome measures as well as clinical outcomes including ROM, adverse events and all-cause reoperation rates., Results: Forty-eight studies met the inclusion criteria and included 1838 acute, intra-articular distal humeral fractures. There was no clinically important difference in patient-reported pain and function measured on the Mayo Elbow Performance Score (TEA = 89.3 (SD 20.0), Hemi = 88.4 (SD 10.6), internal fixation = 85.0 (SD 14.7), non-operative = 85.1 (SD 11.0))., Discussion: Each of the treatment modalities studies resulted in a reasonable level of elbow function. The included studies were largely non-comparative and at considerable risk of bias. As elbow replacement surgery becomes centralised in the UK, there is a real need for high-quality comparative research studies to inform practice., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Published
2024
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14. Arthroscopic capsular shift surgery in patients with atraumatic shoulder joint instability: a randomised, placebo-controlled trial.

Author

Jaggi A, Herbert RD, Alexander S, Majed A, Butt D, Higgs D, Rudge W, and Ginn KA

Subjects
Humans, Adolescent, Adult, Arthroscopy, Shoulder, Shoulder Pain surgery, Treatment Outcome, Joint Instability surgery, Shoulder Joint surgery
Abstract

Objectives: To determine the effect of arthroscopic capsular shift surgery on pain and functional impairment for people with atraumatic shoulder (glenohumeral) joint instability., Methods: We conducted a randomised, placebo-controlled clinical trial in a specialist secondary care facility. Patients aged 18 years and over who reported insecurity (apprehension) in their shoulder joint and had evidence of capsulolabral damage on arthroscopic examination were included. Patients were excluded if their shoulder apprehension symptoms were precipitated by a high velocity shoulder injury, they had bony or neural damage, a rotator cuff or labral tear, or previous surgery on the symptomatic shoulder. Sixty-eight participants were randomised and received diagnostic arthroscopy, followed by arthroscopic capsular shift or diagnostic arthroscopy alone. All participants received the same postoperative clinical care. The primary outcome was pain and functional impairment measured with the Western Ontario Shoulder Instability Index. The prespecified minimum clinically important effect was a reduction in pain and disability of 10.4 points., Results: Mean reductions in pain and functional impairment for both groups were similar. Compared with diagnostic arthroscopy, arthroscopic capsular shift increased pain and functional impairment by means of 5 points (95% CI -6 to 16 points) at 6 months, 1 point (95% CI -11 to 13 points) at 12 months and 2 points (95% CI -12 to 17 points) at 24 months., Conclusions: Compared with diagnostic arthroscopy alone, arthroscopic capsular shift confers, at best, only minimal clinically important benefit in the medium term., Trial Registration Number: NCT01751490., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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15. Understanding fundamental principles of enhancer biology at a model locus: Analysing the structure and function of an enhancer cluster at the α-globin locus.

Author

Kassouf M, Ford S, Blayney J, and Higgs D

Subjects
Animals, Transcription Factors metabolism, Promoter Regions, Genetic genetics, Biology, Mammals genetics, Enhancer Elements, Genetic genetics, alpha-Globins genetics
Abstract

Despite ever-increasing accumulation of genomic data, the fundamental question of how individual genes are switched on during development, lineage-specification and differentiation is not fully answered. It is widely accepted that this involves the interaction between at least three fundamental regulatory elements: enhancers, promoters and insulators. Enhancers contain transcription factor binding sites which are bound by transcription factors (TFs) and co-factors expressed during cell fate decisions and maintain imposed patterns of activation, at least in part, via their epigenetic modification. This information is transferred from enhancers to their cognate promoters often by coming into close physical proximity to form a 'transcriptional hub' containing a high concentration of TFs and co-factors. The mechanisms underlying these stages of transcriptional activation are not fully explained. This review focuses on how enhancers and promoters are activated during differentiation and how multiple enhancers work together to regulate gene expression. We illustrate the currently understood principles of how mammalian enhancers work and how they may be perturbed in enhanceropathies using expression of the α-globin gene cluster during erythropoiesis, as a model., (© 2023 The Authors. BioEssays published by Wiley Periodicals LLC.)

Published
2023
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16. Infectious pancreatic necrosis virus (IPNV) recombinant viral protein 1 (VP1) and VP2-Flagellin fusion protein elicit distinct expression profiles of cytokines involved in type 1, type 2, and regulatory T cell response in rainbow trout (Oncorhynchus mykiss).

Author

Wong-Benito V, Barraza F, Trujillo-Imarai A, Ruiz-Higgs D, Montero R, Sandino AM, Wang T, Maisey K, Secombes CJ, and Imarai M

Subjects
Animals, Flagellin pharmacology, Transforming Growth Factor beta1, Cytokines genetics, Interleukin-4, T-Lymphocytes, Regulatory, Immunologic Factors, Viral Proteins, Infectious pancreatic necrosis virus, Oncorhynchus mykiss, Birnaviridae Infections, Fish Diseases
Abstract

In this study, we examined the cytokine immune response against two proteins of infectious pancreatic necrosis virus (IPNV) in rainbow trout (Oncorhynchus mykiss), the virion-associated RNA polymerase VP1 and VP2-Flagellin (VP2-Flg) fusion protein. Since VP1 is not a structural protein, we hypothesize it can induce cellular immunity, an essential mechanism of the antiviral response. At the same time, the fusion construction VP2-Flg could be highly immunogenic due to the presence of the flagellin used as an adjuvant. Fish were immunized with the corresponding antigen in Montanide™, and the gene expression of a set of marker genes of Th1, Th2, and the immune regulatory response was quantified in the head kidney of immunized and control fish. Results indicate that VP1 induced upregulation of ifn-γ, il-12p40c, il-4/13a, il-4/13b2, il-10a, and tgf-β1 in immunized fish. Expression of il-2a did not change in treated fish at the times tested. The antigen-dependent response was analysed by in vitro restimulation of head kidney leukocytes. In this assay, the group of cytokines upregulated after VP1-restimulation was consistent with those upregulated in the head kidney in vivo. Interestingly, VP1 induced il-2a expression after in vitro restimulation. The analysis of sorted lymphocytes showed that the increase of cytokines occurred in CD4-1 + T cells suggesting that Th differentiation happens in response to VP1. This is also consistent with the expression of t-bet and gata3, the master regulators for Th1/Th2 differentiation in the kidneys of immunized animals. A different cytokine expression profile was found after VP2-Flg administration, i.e., upregulation occurs for ifn-γ, il-4/13a, il-10a, and tgf-β1, while down-regulation was observed in il-4/13b2 and il-2a. The cytokine response was due to flagellin; only the il-2a effect was dependent upon VP2 in the fusion protein. To the best of our knowledge this study reports for the first-time characteristics of the adaptive immune response induced in response to IPNV VP1 and the fusion protein VP2-Flg in fish. VP1 induces cytokines able to trigger the humoral and cell-mediated immune response in rainbow trout. The analysis of the fish response against VP2-Flg revealed the immunogenic properties of Aeromonas salmonicida flagellin, which can be further tested for adjuvanticity. The novel immunogenic effects of VP1 in rainbow trout open new opportunities for further IPNV vaccine development using this viral protein., (Copyright © 2022. Published by Elsevier Ltd.)

Published
2022
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17. Surgeon involvement in clinical coding to improve data accuracy and remuneration in a shoulder and elbow unit.

Author

Kyriacou S, Butt D, Rudge W, Higgs D, Falworth M, and Majed A

Abstract

Background: Clinical coders are dependent on clear data regarding diagnoses and procedures to generate an accurate representation of clinical activity and ensure appropriate remuneration is received. The accuracy of this process may potentially be improved by collaboration with the surgical team., Methods: Between November 2017 and November 2019, 19 meetings took place between the Senior Clinical Fellow of our tertiary Shoulder & Elbow Unit and the coding validation lead of our Trust. At each meeting, the Clinical Fellow assessed the operative note of cases in which uncertainty existed as to the most suitable clinical codes to apply and selected the codes which most accurately represented the operative intervention performed., Results: Over a 24-month period, clinical coding was reviewed in 153 cases (range 3-14 per meeting, mean 8). Following review, the clinical coding was amended in 102 (67%) of these cases. A total of £115,160 additional income was generated as a result of this process (range £1677-£15,796 per meeting, mean £6061). Only 6 out of 28 (21%) cases initially coded as arthroscopic sub-acromial decompressions were correctly coded as such., Discussion: Surgeon input into clinical coding greatly improves data quality and increases remuneration received for operative interventions performed., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The British Elbow & Shoulder Society.)

Published
2022
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