Search results
Found 9875 matches for
Dr Fiona Watt wins prestigious Michael Mason Prize 2016.
Degeneration of cortical function in the Royal College of Surgeons rat.
The purpose of the current study was to determine the progress of cortical functional degeneration in the Royal College of Surgeons (RCS) rat. Cortical responses were measured with optical imaging of intrinsic signals using gratings of various spatial frequencies. Subsequently, electrophysiological recordings were also taken across cortical layers in response to a pulse of broad-spectrum light. We found significant degeneration in the cortical processing of visual information as early as 4 weeks of age. These results show that degeneration in the cortical response of the RCS rat starts before development has been properly completed.
Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells.
Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.
Factors associated with adherence and persistence to bisphosphonate therapy in osteoporosis: a cross-sectional survey.
OBJECTIVE: To determine the factors associated with adherence and persistence to bisphosphonate therapy in osteoporosis. DESIGN: Cross-sectional survey. SETTING: National survey in the UK. PARTICIPANTS: Participants were recruited through the National Osteoporosis Society and advertisements in the press and on the radio and included 533 women over age 50 with osteoporosis who were currently taking or had taken bisphosphonate therapy within the previous 12 months. MAIN OUTCOME MEASURES: Self-reported factors influencing adherence and persistence to bisphosphonate therapy in osteoporosis: fracture history, pain, practical difficulties taking medication (frequency of dosing, dealing with comedications, impact on daily routine), perceptions of therapy, and concerns about bisphosphonate therapy. RESULTS: Adherence to bisphosphonate therapy was 48% and was associated with previous fracture [odds ratio (OR) 1.62, 95% confidence interval (CI) 1.14-3.02], concerns about medication (OR 1.49, 95% CI 1.01-2.20), and less dissatisfaction with medication (OR 0.65, 95% CI 0.44-0.97). Nonpersistence was associated with dissatisfaction with medication (hazard ratio (HR) 1.83, 95% CI 1.38-2.43), side effects (HR 3.69, 95% CI 2.74-4.97), and concerns about bisphosphonate therapy (HR 2.21, 95% CI 1.48-3.30). For both daily (HR 1.53, 95% CI 1.1-2.33) and weekly bisphosphonates (HR 1.90, 95% CI 1.17-3.07), practical difficulties taking bisphosphonate medication-in particular, too frequent dosing-were associated with nonpersistence. CONCLUSIONS: Self-reported nonadherence to daily and weekly bisphosphonates is independent of the decision to stop taking treatment (nonpersistence). Nonpersistence is associated with side effects and other factors that could be modified in clinical practice through education, information, and concordant partnerships.
Rhodanine-3-acetic acid derivatives as inhibitors of fungal protein mannosyl transferase 1 (PMT1).
The first inhibitors of fungal protein: mannosyl transferase 1 (PMT1) are described. They are based upon rhodanine-3-acetic acid and several compounds have been identified, for example, 5-[[3-(1-phenylethoxy)-4-(2-phenylethoxy)phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid (5a), which inhibit Candida albicans PMT1 with IC(50)s in the range 0.2-0.5 microM. Members of the series are effective in inducing changes in morphology of C. albicans in vitro that have previously been associated with loss of the transferase activity. These compounds could serve as useful tools for studying the effects of protein O-mannosylation and its relevance in the search for novel antifungal agents.
Global gene expression responses of fission yeast to ionizing radiation.
A coordinated transcriptional response to DNA-damaging agents is required to maintain genome stability. We have examined the global gene expression responses of the fission yeast Schizosaccharomyces pombe to ionizing radiation (IR) by using DNA microarrays. We identified approximately 200 genes whose transcript levels were significantly altered at least twofold in response to 500 Gy of gamma IR in a temporally defined manner. The majority of induced genes were core environmental stress response genes, whereas the remaining genes define a transcriptional response to DNA damage in fission yeast. Surprisingly, few DNA repair and checkpoint genes were transcriptionally modulated in response to IR. We define a role for the stress-activated mitogen-activated protein kinase Sty1/Spc1 and the DNA damage checkpoint kinase Rad3 in regulating core environmental stress response genes and IR-specific response genes, both independently and in concert. These findings suggest a complex network of regulatory pathways coordinate gene expression responses to IR in eukaryotes.
Investigating the lymphatic system in intestinal inflammation
We set out to understand the colonic lymphatic vasculature in the context of outflow from the colon, with the ambition of using this knowledge to develop methods to promote exit of inflammatory cells from the tissue as an alternative way to treat patients with inflammatory bowel disease. Our studies converged on the identification of tissue folds as central anatomical units that orchestrate interstitial fluid outflow from the colon. We observed that the luminal surface of the mammalian colon is characterised by undulations of the mucosa and submucosa forming tissue folds. In humans these included haustral folds and intrahaustral folds of lesser prominence between muscular bands of taenia coli. Mice lacked taenia coli and haustra but nonetheless possessed folds, especially in the proximal colon. The functional significance of these colonic tissue undulations, beyond increasing surface area for absorption, had not previously been determined. Here, through murine in vivo and 3D imaging studies, we show that tissue folds orchestrated the collection and outflow of interstitial fluid from the colon. We demonstrate that lymphatics line the base of colonic crypts and specifically branched toward the epithelium within folds. Colonic folds functioned as reservoirs feeding lymphatic and venous outflow, and phagocytic scavenging by fold-associated mononuclear phagocytes augmented this reservoir property. Colonic lymphoid follicles were enriched within these tissue folds, surrounded by lymphatics and postcapillary venules. Human colonic lymphoid follicles were likewise positioned within the elevation of tissue folds. Our findings suggest that colonic folds are distinct anatomical units conserved across species that organise uptake, immunosurveillance, and outflow of interstitial cargo, while restraining the spread of inflammation. Indeed, the loss of tissue folds during ulcerative colitis may facilitate distal-to-proximal spread of pathology.
RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1.
Natural killer (NK) cells use inhibitory and activating immune receptors to differentiate between human cells and pathogens. Signalling by these receptors determines whether an NK cell becomes activated and destroys a target cell. In some cases, such as killer immunoglobulin-like receptors, immune receptors are found in pairs, with inhibitory and activating receptors containing nearly identical extracellular ligand-binding domains coupled to different intracellular signalling domains1. Previous studies showed that repetitive interspersed family (RIFIN) proteins, displayed on the surfaces of Plasmodium falciparum-infected erythrocytes, can bind to inhibitory immune receptors and dampen NK cell activation2,3, reducing parasite killing. However, no pathogen-derived ligand has been identified for any human activating receptor. Here we identified a clade of RIFINs that bind to inhibitory immune receptor KIR2DL1 more strongly than KIR2DL1 binds to the human ligand (MHC class I). This interaction mediates inhibitory signalling and suppresses the activation of KIR2DL1-expressing NK cells. We show that KIR2DL1-binding RIFINs are abundant in field-isolated strains from both Africa and Asia and reveal how the two RIFINs bind to KIR2DL1. The RIFIN binding surface of KIR2DL1 is conserved in the cognate activating immune receptor KIR2DS1. We find that KIR2DL1-binding RIFINs can also bind to KIR2DS1, resulting in the activation of KIR2DS1-expressing NK cells. This study demonstrates that activating killer immunoglobulin-like receptors can recruit NK cells to target a pathogen and reveals a potential role for activating immune receptors in controlling malaria infection.
The Arthroplasty Candidacy Help Engine tool to select candidates for hip and knee replacement surgery: development and economic modelling
Background There is no good evidence to support the use of patient-reported outcome measures (PROMs) in setting preoperative thresholds for referral for hip and knee replacement surgery. Despite this, the practice is widespread in the NHS. Objectives/research questions Can clinical outcome tools be used to set thresholds for hip or knee replacement? What is the relationship between the choice of threshold and the cost-effectiveness of surgery? Methods A systematic review identified PROMs used to assess patients undergoing hip/knee replacement. Their measurement properties were compared and supplemented by analysis of existing data sets. For each candidate score, we calculated the absolute threshold (a preoperative level above which there is no potential for improvement) and relative thresholds (preoperative levels above which individuals are less likely to improve than others). Owing to their measurement properties and the availability of data from their current widespread use in the NHS, the Oxford Knee Score (OKS) and Oxford Hip Score (OHS) were selected as the most appropriate scores to use in developing the Arthroplasty Candidacy Help Engine (ACHE) tool. The change in score and the probability of an improvement were then calculated and modelled using preoperative and postoperative OKS/OHSs and PROM scores, thereby creating the ACHE tool. Markov models were used to assess the cost-effectiveness of total hip/knee arthroplasty in the NHS for different preoperative values of OKS/OHSs over a 10-year period. The threshold values were used to model how the ACHE tool may change the number of referrals in a single UK musculoskeletal hub. A user group was established that included patients, members of the public and health-care representatives, to provide stakeholder feedback throughout the research process. Results From a shortlist of four scores, the OHS and OKS were selected for the ACHE tool based on their measurement properties, calculated preoperative thresholds and cost-effectiveness data. The absolute threshold was 40 for the OHS and 41 for the OKS using the preferred improvement criterion. A range of relative thresholds were calculated based on the relationship between a patient’s preoperative score and their probability of improving after surgery. For example, a preoperative OHS of 35 or an OKS of 30 translates to a 75% probability of achieving a good outcome from surgical intervention. The economic evaluation demonstrated that hip and knee arthroplasty cost of < £20,000 per quality-adjusted life-year for patients with any preoperative score below the absolute thresholds (40 for the OHS and 41 for the OKS). Arthroplasty was most cost-effective for patients with lower preoperative scores. Limitations The ACHE tool supports but does not replace the shared decision-making process required before an individual decides whether or not to undergo surgery. Conclusion The OHS and OKS can be used in the ACHE tool to assess an individual patient’s suitability for hip/knee replacement surgery. The system enables evidence-based and informed threshold setting in accordance with local resources and policies. At a population level, both hip and knee arthroplasty are highly cost-effective right up to the absolute threshold for intervention. Our stakeholder user group felt that the ACHE tool was a useful evidence-based clinical tool to aid referrals and that it should be trialled in NHS clinical practice to establish its feasibility. Future work Future work could include (1) a real-world study of the ACHE tool to determine its acceptability to patients and general practitioners and (2) a study of the role of the ACHE tool in supporting referral decisions.
Who gets referred for knee or hip replacement? A theoretical model of the potential impact of evidence-based referral thresholds using data from a retrospective review of clinic records from an English musculoskeletal referral hub.
OBJECTIVES: To estimate the relationship between patient characteristics and referral decisions made by musculoskeletal hubs, and to assess the possible impact of an evidence-based referral tool. DESIGN: Retrospective analysis of medical records and decision tree model evaluating policy changes using local and national data. SETTING: One musculoskeletal interface clinic (hub) in England. PARTICIPANTS: 922 adults aged ≥50 years referred by general practitioners with symptoms of knee or hip osteoarthritis. INTERVENTIONS: We assessed the current frequency and determinants of referrals from one hub and the change in referrals that would occur at this centre and nationally if evidence-based thresholds for referral (Oxford Knee and Hip Scores, OKS/OHS) were introduced. MAIN OUTCOME MEASURE: OKS/OHS, referrals for surgical assessment, referrals for arthroplasty, costs and quality-adjusted life years. RESULTS: Of 110 patients with knee symptoms attending face-to-face hub consultations, 49 (45%) were referred for surgical assessment; the mean OKS for these 49 patients was 18 (range: 1-41). Of 101 hip patients, 36 (36%) were referred for surgical assessment (mean OHS: 21, range: 5-44). No patients referred for surgical assessment were above previously reported economic thresholds for OKS (43) or OHS (45). Setting thresholds of OKS ≤31 and OHS ≤35 might have resulted in an additional 22 knee referrals and 26 hip referrals in our cohort. Extrapolating hub results across England suggests a possible increase in referrals nationally, of around 13 000 additional knee replacements and 4500 additional hip replacements each year. CONCLUSIONS: Musculoskeletal hubs currently consider OKS/OHS and other factors when making decisions about referral to secondary care for joint replacement. Those referred typically have low OHS/OKS, and introducing evidence-based OKS/OHS thresholds would prevent few inappropriate (high-functioning, low-pain) referrals. However, our findings suggest that some patients not currently referred could benefit from arthroplasty based on OKS/OHS. More research is required to explore other important patient characteristics currently influencing hub decisions.
Lower limb arthroplasty: can we produce a tool to predict outcome and failure, and is it cost-effective? An epidemiological study
Background Although hip and knee arthroplasties are considered to be common elective cost-effective operations, up to one-quarter of patients are not satisfied with the operation. A number of risk factors for implant failure are known, but little is known about the predictors of patient-reported outcomes.
Findings from the Patch Augmented Rotator Cuff Surgery (PARCS) Feasibility Study
<jats:title>Abstract</jats:title> <jats:p>BackgroundA rotator cuff tear is a common disabling shoulder problem. Symptoms include pain, weakness, lack of mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a pressing need to improve the outcome of rotator cuff surgery. The use of patch augmentation to provide support to the healing process and improve patient outcomes holds new promise. Different materials (e.g. human/animal skin or intestine tissue, and completely synthetic materials) and processes (e.g. woven or a mesh) have been used to produce patches. However, clinical evidence on their use is limited. The Patch Augmented Rotator Cuff Surgery (PARCS) feasibility study aimed to determine the design of a definitive randomised controlled trial (RCT) assessing the effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible.MethodsA mixed methods feasibility study of a RCT. The project involved six stages: a systematic review of clinical evidence; a survey of the British Elbow and Shoulder (BESS) society’s surgical membership; a survey of surgeon trialists; focus groups and interviews with stakeholders; a two-round Delphi study administered via online questionnaires; and a two-day Consensus Meeting. ResultsThe BESS surgeons’ survey identified a variety of patches in use (105 (21%) responses received). Twenty-four surgeons (77%) completed the trialist survey relating to trial design. Four focus groups were conducted involving 24 stakeholders. Twenty-nine (67% of invited) individuals took part in the Delphi. Differing views were held on a number of aspects including the appropriate patient population for trial participation. Agreement on the key research questions and the outline of two potential RCTs were achieved through the Delphi study and the consensus meeting). ConclusionsRandomised comparisons of on-lay patch use for completed rotator cuff repairs, and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. The main limitation was that the findings were influenced by the participants, who might not necessarily reflect all stakeholders.</jats:p>
In vitro evaluation of the response of human tendon-derived stromal cells to a novel electrospun suture for tendon repair.
Recurrent tears after surgical tendon repair remain common. Repair failures can be partly attributed to the use of sutures not designed for the tendon cellular niche nor for the promotion of repair processes. Synthetic electrospun materials can mechanically support the tendon whilst providing topographical cues that regulate cell behaviour. Here, a novel electrospun suture made from twisted polydioxanone (PDO) polymer filaments is compared to PDS II, a clinically-used PDO suture currently utilised in tendon repair. We evaluated the ability of these sutures to support the attachment and proliferation of human tendon-derived stromal cells using PrestoBlue and Scanning Electron Microscopy. Suture surface chemistry was analysed using X-ray Photoelectron Spectroscopy. Bulk RNA-Seq interrogated the transcriptional response of primary tendon-derived stromal cells to sutures after 14 days. Electrospun suture showed increased initial cell attachment and a stronger transcriptional response compared to PDS II, with relative enrichment of pathways including mTorc1 signalling and depletion of epithelial mesenchymal transition. Neither suture induced transcriptional upregulation of inflammatory pathways compared to baseline. Twisted electrospun sutures therefore show promise in improving outcomes in surgical tendon repair by allowing increased cell attachment whilst maintaining an appropriate tissue response.
Age and frailty are independently associated with increased COVID-19 mortality and increased care needs in survivors: results of an international multi-centre study.
INTRODUCTION: Increased mortality has been demonstrated in older adults with coronavirus disease 2019 (COVID-19), but the effect of frailty has been unclear. METHODS: This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS) and delirium on risk of increased care requirements on discharge, adjusting for the same variables. RESULTS: Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, interquartile range [IQR] 54-83; 55.2% male). The risk of death increased independently with increasing age (>80 versus 18-49: hazard ratio [HR] 3.57, confidence interval [CI] 2.54-5.02), frailty (CFS 8 versus 1-3: HR 3.03, CI 2.29-4.00) inflammation, renal disease, cardiovascular disease and cancer, but not delirium. Age, frailty (CFS 7 versus 1-3: odds ratio 7.00, CI 5.27-9.32), delirium, dementia and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. CONCLUSION: Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.
