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Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials.
BACKGROUND: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. METHODS: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. FINDINGS: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. INTERPRETATION: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. FUNDING: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. VIDEO ABSTRACT.
A novel variant in GLIS3 is associated with osteoarthritis.
OBJECTIVES: Osteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date. METHODS: We carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR. RESULTS: We detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10-8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes. CONCLUSIONS: We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.
When should placebo surgery as a control in clinical trials be carried out?
Placebo surgery – often maligned as ‘sham surgery’ – is a tough sell to patients and to many clinicians. But could surgical research benefit from increased use of placebo control groups?
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.
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.
Comparison of surgical or non-surgical management for non-acute anterior cruciate ligament injury: the ACL SNNAP RCT.
BACKGROUND: Anterior cruciate ligament injury of the knee is common and leads to decreased activity and risk of secondary osteoarthritis of the knee. Management of patients with a non-acute anterior cruciate ligament injury can be non-surgical (rehabilitation) or surgical (reconstruction). However, insufficient evidence exists to guide treatment. OBJECTIVE(S): To determine in patients with non-acute anterior cruciate ligament injury and symptoms of instability whether a strategy of surgical management (reconstruction) without prior rehabilitation was more clinically and cost-effective than non-surgical management (rehabilitation). DESIGN: A pragmatic, multicentre, superiority, randomised controlled trial with two-arm parallel groups and 1:1 allocation. Due to the nature of the interventions, no blinding could be carried out. SETTING: Twenty-nine NHS orthopaedic units in the United Kingdom. PARTICIPANTS: Participants with a symptomatic (instability) non-acute anterior cruciate ligament-injured knee. INTERVENTIONS: Patients in the surgical management arm underwent surgical anterior cruciate ligament reconstruction as soon as possible and without any further rehabilitation. Patients in the rehabilitation arm attended physiotherapy sessions and only were listed for reconstructive surgery on continued instability following rehabilitation. Surgery following initial rehabilitation was an expected outcome for many patients and within protocol. MAIN OUTCOME MEASURES: The primary outcome was the Knee Injury and Osteoarthritis Outcome Score 4 at 18 months post randomisation. Secondary outcomes included return to sport/activity, intervention-related complications, patient satisfaction, expectations of activity, generic health quality of life, knee-specific quality of life and resource usage. RESULTS: Three hundred and sixteen participants were recruited between February 2017 and April 2020 with 156 randomised to surgical management and 160 to rehabilitation. Forty-one per cent (n = 65) of those allocated to rehabilitation underwent subsequent reconstruction within 18 months with 38% (n = 61) completing rehabilitation and not undergoing surgery. Seventy-two per cent (n = 113) of those allocated to surgery underwent reconstruction within 18 months. Follow-up at the primary outcome time point was 78% (n = 248; surgical, n = 128; rehabilitation, n = 120). Both groups improved over time. Adjusted mean Knee Injury and Osteoarthritis Outcome Score 4 scores at 18 months had increased to 73.0 in the surgical arm and to 64.6 in the rehabilitation arm. The adjusted mean difference was 7.9 (95% confidence interval 2.5 to 13.2; p = 0.005) in favour of surgical management. The per-protocol analyses supported the intention-to-treat results, with all treatment effects favouring surgical management at a level reaching statistical significance. There was a significant difference in Tegner Activity Score at 18 months. Sixty-eight per cent (n = 65) of surgery patients did not reach their expected activity level compared to 73% (n = 63) in the rehabilitation arm. There were no differences between groups in surgical complications (n = 1 surgery, n = 2 rehab) or clinical events (n = 11 surgery, n = 12 rehab). Of surgery patients, 82.9% were satisfied compared to 68.1% of rehabilitation patients. Health economic analysis found that surgical management led to improved health-related quality of life compared to non-surgical management (0.052 quality-adjusted life-years, p = 0.177), but with higher NHS healthcare costs (£1107, p
Surgical fixation with K-wires versus casting in adults with fracture of distal radius: DRAFFT2 multicentre randomised clinical trial.
OBJECTIVE: To assess wrist function, quality of life, and complications in adult patients with a dorsally displaced fracture of the distal radius, treated with either a moulded cast or surgical fixation with K-wires. DESIGN: Multicentre randomised clinical superiority trial, SETTING: 36 hospitals in the UK National Health Service (NHS). PARTICIPANTS: 500 adults aged 16 or over with a dorsally displaced fracture of the distal radius, randomised after manipulation of their fracture (255 to moulded cast; 245 to surgical fixation). INTERVENTIONS: Manipulation and moulded cast was compared with manipulation and surgical fixation with K-wires plus cast. Details of the application of the cast and the insertion of the K-wires were at the discretion of the treating surgeon, according to their normal clinical practice. MAIN OUTCOME MEASURES: The primary outcome measure was the Patient Rated Wrist Evaluation (PRWE) score at 12 months (five questions about pain and 10 about function and disability; overall score out of 100 (best score=0 and worst score=100)). Secondary outcomes were PRWE score at three and six months, quality of life, and complications, including the need for surgery due to loss of fracture position in the first six weeks. RESULTS: The mean age of participants was 60 years and 417 (83%) were women; 395 (79%) completed follow-up. No statistically significant difference in the PRWE score was seen at 12 months (cast group (n=200), mean 21.2 (SD 23.1); K-wire group (n=195), mean 20.7 (22.3); adjusted mean difference -0.34 (95% confidence interval -4.33 to 3.66), P=0.87). No difference was seen at earlier time points. In the cast group, 33 (13%) of participants needed surgical fixation for loss of fracture position in the first six weeks compared with one revision surgery in the K-wire group (odds ratio 0.02, 95% confidence interval 0.001 to 0.10). CONCLUSIONS: Among patients with a dorsally displaced distal radius fracture that needed manipulation, surgical fixation with K-wires did not improve patients' wrist function at 12 months compared with a cast. TRIAL REGISTRATION: ISRCTN registry ISRCTN11980540.
SPiRIT study protocol (Shoulder Pain: Randomised trial of Injectable Treatments): a randomised feasibility and pilot study of autologous protein solution (APS) vs corticosteroids for treating subacromial shoulder pain.
BACKGROUND: The management of subacromial shoulder pain represents a significant challenge and is typically managed through either physiotherapy, joint injection or surgical intervention. Recent surgical trials have questioned the efficacy and there is a need to improve the evidence base for the non-surgical management of this condition. The study aims to provide evidence of the feasibility of conducting a randomised controlled trial to compare the efficacy of autologous protein solution (APS) against the current standard of care, corticosteroid injection (CSI) for subacromial shoulder pain. Autologous protein solution (APS) is a blood-derived biological injection which has been shown to have anti-inflammatory effects. METHODS: A parallel-group two-arm randomised control trial will be conducted, comparing APS and CSI for shoulder pain. Fifty patients will be recruited. Feasibility will be assessed by examination of the conversion rate of eligible participants to the total number of participants recruited, whether it is possible to collect the appropriate outcome measures and the levels of retention/data compliance at follow-up dates. DISCUSSION: CSI is the mainstay of conservative management of subacromial shoulder pain. Trials and systematic reviews have reported differing conclusions, but the consensus view is that any benefits seen from CSI use are most likely to be short-term and there remains a significant number of patients who go on to have surgical intervention despite CSI. Biological injections, such as APS are being increasingly used, in the anticipation they may offer improved longer lasting outcomes for shoulder pain. However, the evidence to demonstrate the comparative efficacy of CSI versus APS does not currently exist. If feasible, a fully powered study will offer clarity to the treatment pathway of thousands of patients each year with subacromial pain. TRIAL REGISTRATION: The study is funded by the National Institute for Health Research-Research for Patient Benefit, NIHR 201473, Trial Registration Number (ISRCTN12536844: SPiRIT. Shoulder pain: randomised trial of injectable treatments-date of Registration 15/9/2021). Protocol Version V1.0_30Jul2021. IRAS Project ID: 294,982.
Proresolving mediators LXB4 and RvE1 regulate inflammation in stromal cells from patients with shoulder tendon tears
ABSTRACTTendon stromal cells isolated from patients with chronic shoulder rotator-cuff tendon tears show dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation, therefore new therapeutic approaches targeting tendon stromal cells are required. We determined if two specialised pro-resolving mediators (SPM) LXB4 and RvE1, modulated the bioactive lipid mediator (LM) profiles of IL-1β stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also determined if LXB4/RvE1 treatments moderated the pro-inflammatory phenotype of tendon tear stromal cells. Incubation of IL-1β treated patient derived tendon cells in LXB4/RvE1 upregulated concentrations of SPM. RvE1 treatment specifically increased 15-epi-LXB4 and regulated PGF2α. LXB4 or RvE1 also induced expression of the SPM biosynthetic enzymes 12-liopxygeanse (ALOX12), and ALOX15. RvE1 treatment upregulated proresolving receptor ERV1 compared to vehicle treated cells. Incubation in LXB4 or RvE1 moderated the proinflammatory phenotype of patient derived tendon tear cells, regulating markers of tendon inflammation, including Podoplanin, CD90, STAT-1 and IL-6. These treatments also suppressed JNK1/2/3, Lyn, STAT-3 and STAT-6 and induced p70s6kinase phospho-kinase signalling. LXB4 and RvE1 counter-regulate inflammatory processes in tendon stromal cells, supporting the role of these molecules as potential therapeutics to resolve tendon inflammation.
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.
Moulded cast compared with K-wire fixation after manipulation of an acute dorsally displaced distal radius fracture: the DRAFFT 2 RCT.
BACKGROUND: Patients with a displaced fracture of the distal radius are frequently offered surgical fixation. Manipulation of the fracture and moulded plaster casting is an alternative treatment that avoids metal implants, but evidence of its effectiveness is lacking. OBJECTIVE: To compare functional outcomes, quality-of-life outcomes, complications and resource use among patients with a dorsally displaced fracture of the distal radius treated with manipulation and surgical fixation with Kirschner wires (K-wires) and those treated with manipulation and moulded cast. DESIGN: Pragmatic, superiority, multicentre, randomised controlled trial with a health economic evaluation. SETTING: A total of 36 orthopaedic trauma centres in the UK NHS. PARTICIPANTS: Patients (aged ≥ 16 years) treated for an acute dorsally displaced fracture of the distal radius were potentially eligible. Patients were excluded if their injury had occurred > 2 weeks previously, if the fracture was open, if it extended > 3 cm from the radiocarpal joint or if it required open reduction, or if the participant was unable to complete questionnaires. INTERVENTIONS: Participants were randomly assigned in theatre (1 : 1) to receive a moulded cast (i.e. the cast group) or surgical fixation with K-wires (i.e. the K-wire group) after fracture manipulation. MAIN OUTCOME MEASURES: The primary outcome measure was the Patient-Rated Wrist Evaluation score at 12 months, analysed on an intention-to-treat basis. Health-related quality of life was recorded using the EuroQol-5 Dimensions, five-level version, and resource use was recorded from a health and personal social care perspective. RESULTS: Between January 2017 and March 2019, 500 participants (mean age 60 years, 83% women) were randomly allocated to receive a moulded cast (n = 255) or surgical fixation with K-wire (n = 245) following a manipulation of their fracture. A total of 395 (80%) participants were included in the primary analysis at 12 months. There was no difference in the Patient-Rated Wrist Evaluation score at 1 year post randomisation [cast group: n = 200, mean score 21.2 (standard deviation 23.1); K-wire group: n = 195, mean score 20.7 (standard deviation 22.3); adjusted mean difference -0.34 (95% confidence interval -4.33 to 3.66); p = 0.87]. A total of 33 (13%) participants in the cast group required surgical fixation for loss of fracture position in the first 6 weeks, compared with one participant in the K-wire group (odds ratio 0.02, 95% confidence interval 0.001 to 0.10). The base-case cost-effectiveness analysis showed that manipulation and surgical fixation with K-wires had a higher mean cost than manipulation and a moulded cast, despite similar mean effectiveness. The use of K-wires is unlikely to be cost-effective, and sensitivity analyses found this result to be robust. LIMITATIONS: Because the interventions were identifiable, neither patients nor clinicians could be blind to their treatment. CONCLUSIONS: Surgical fixation with K-wires was not found to be superior to moulded casting following manipulation of a dorsally displaced fracture of the distal radius, as measured by Patient-Rated Wrist Evaluation score. However, one in eight participants treated in a moulded cast required surgery for loss of fracture reduction in the first 6 weeks. After a successful closed reduction, clinicians may consider a moulded cast as a safe and cost-effective alternative to surgical fixation with K-wires. FUTURE WORK: Further research should focus on optimal techniques for immobilisation and manipulation of this type of fracture, including optimal analgesia, and for rehabilitation of the patient after immobilisation. TRIAL REGISTRATION: This trial is registered as ISRCTN11980540 and UKCRN Portfolio 208830. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 11. See the NIHR Journals Library website for further project information.
Interleukin-17A Causes Osteoarthritis-Like Transcriptional Changes in Human Osteoarthritis-Derived Chondrocytes and Synovial Fibroblasts In Vitro.
Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and synovial fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptor A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-κB. Incubation of chondrocytes and synovial fibroblasts with anti-IL-17A monoclonal antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Future studies should further investigate the role of IL-17A in the OA joint to establish whether anti-IL-17 treatment could be a potential therapeutic option in OA patients with an inflammatory phenotype.
Cost-effectiveness analysis of a pragmatic randomized trial evaluating surgical reconstruction versus rehabilitation in patients with long-standing anterior cruciate ligament injury.
AIMS: The aim of this study was to estimate the incremental use of resources, costs, and quality of life outcomes associated with surgical reconstruction compared to rehabilitation for long-standing anterior cruciate ligament (ACL) injury in the NHS, and to estimate its cost-effectiveness. METHODS: A total of 316 patients were recruited and randomly assigned to either surgical reconstruction or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment). Healthcare resource use and health-related quality of life data (EuroQol five-dimension five-level health questionnaire) were collected in the trial at six, 12, and 18 months using self-reported questionnaires and medical records. Using intention-to-treat analysis, differences in costs, and quality-adjusted life years (QALYs) between treatment arms were estimated adjusting for baseline differences and following multiple imputation of missing data. The incremental cost-effectiveness ratio (ICER) was estimated as the difference in costs divided by the difference in QALYs between reconstruction and rehabilitation. RESULTS: At 18 months, patients in the surgical reconstruction arm reported higher QALYs (0.052 (95% confidence interval (CI) -0.012 to 0.117); p = 0.177) and higher NHS costs (£1,017 (95% CI 557 to 1,476); p < 0.001) compared to rehabilitation. This resulted in an ICER of £19,346 per QALY with the probability of surgical reconstruction being cost-effective of 51% and 72% at a willingness-to-pay threshold of £20,000 and £30,000 per QALY, respectively. CONCLUSION: Surgical reconstruction as a management strategy for patients with long-standing ACL injury is more effective, but more expensive, at 18 months compared to rehabilitation management. In the UK setting, surgical reconstruction is cost-effective.