Skyrmions and the α-particle model of nuclei Battye, Richard A; Manton, Nicholas S; Sutcliffe, Paul M
Proceedings of the Royal Society. A, Mathematical, physical, and engineering sciences,
01/2007, Volume:
463, Issue:
2077
Journal Article
Peer reviewed
Open access
We compute new solutions of the Skyrme model with massive pions. Concentrating on baryon numbers which are multiples of four, we find low-energy Skyrmion solutions that are composed of charge four ...subunits, as in the α-particle model of nuclei. We summarize our current understanding of these solutions, and discuss their relationship to configurations in the α-particle model.
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Healthcare consumers, researchers, patients and policy makers increasingly use systematic reviews (SRs) to aid their decision-making process. However, the conduct of SRs can be a time-consuming and ...resource-intensive task. Often, clinical practice guideline developers or other decision-makers need to make informed decisions in a timely fashion (e.g. outbreaks of infection, hospital-based health technology assessments). Possible approaches to address the issue of timeliness in the production of SRs are to (a) implement process parallelisation, (b) adapt and apply innovative technologies, and/or (c) modify SR processes (e.g. study eligibility criteria, search sources, data extraction or quality assessment). Highly parallelised systematic reviewing requires substantial resources to support a team of experienced information specialists, reviewers and methodologists working alongside with clinical content experts to minimise the time for completing individual review steps while maximising the parallel progression of multiple steps. Effective coordination and management within the team and across external stakeholders are essential elements of this process. Emerging innovative technologies have a great potential for reducing workload and improving efficiency of SR production. The most promising areas of application would be to allow automation of specific SR tasks, in particular if these tasks are time consuming and resource intensive (e.g. language translation, study selection, data extraction). Modification of SR processes involves restricting, truncating and/or bypassing one or more SR steps, which may risk introducing bias to the review findings. Although the growing experiences in producing various types of rapid reviews (RR) and the accumulation of empirical studies exploring potential bias associated with specific SR tasks have contributed to the methodological development for expediting SR production, there is still a dearth of research examining the actual impact of methodological modifications and comparing the findings between RRs and SRs. This evidence would help to inform as to which SR tasks can be accelerated or truncated and to what degree, while maintaining the validity of review findings. Timely delivered SRs can be of value in informing healthcare decisions and recommendations, especially when there is practical urgency and there is no other relevant synthesised evidence.
Aspirin has been recommended for primary prevention of cardiovascular disease (CVD) and cancer, but overall benefits are unclear. We aimed to use novel methods to re-evaluate the balance of benefits ...and harms of aspirin using evidence from randomised controlled trials, systematic reviews and meta-analyses.
Data sources included ten electronic bibliographic databases, contact with experts, and scrutiny of reference lists of included studies. Searches were undertaken in September 2012 and restricted to publications since 2008. Of 2,572 potentially relevant papers 27 met the inclusion criteria. Meta-analysis of control arms to estimate event rates, modelling of all-cause mortality and L'Abbé plots to estimate heterogeneity were undertaken. Absolute benefits and harms were low: 60-84 major CVD events and 34-36 colorectal cancer deaths per 100,000 person-years were averted, whereas 46-49 major bleeds and 68-117 gastrointestinal bleeds were incurred. Reductions in all-cause mortality were minor and uncertain (Hazard Ratio 0.96; 95% CI: 0.90-1.02 at 20 years, Relative Risk RR 0.94, 95% CI: 0.88-1.00 at 8 years); there was a non-significant change in total CVD (RR 0.85, 95% CI: 0.69-1.06) and change in total cancer mortality ranged from 0.76 (95% CI: 0.66-0.88) to 0.93 (95% CI: 0.84-1.03) depending on follow-up time and studies included. Risks were increased by 37% for gastrointestinal bleeds (RR 1.37, 95% CI: 1.15-1.62), 54%-66% for major bleeds (Rate Ratio from IPD analysis 1.54, 95% CI: 1.30-1.82, and RR 1.62, 95% CI: 1.31-2.00), and 32%-38% for haemorrhagic stroke (Rate Ratio from IPD analysis 1.32; 95% CI: 1.00-1.74; RR 1.38; 95% CI: 1.01-1.82).
Findings indicate small absolute effects of aspirin relative to the burden of these diseases. When aspirin is used for primary prevention of CVD the absolute harms exceed the benefits. Estimates of cancer benefit rely on selective retrospective re-analysis of RCTs and more information is needed.
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Rational Skyrmions Harland, Derek; Sutcliffe, Paul
Journal of physics. A, Mathematical and theoretical,
10/2023, Volume:
56, Issue:
42
Journal Article
Peer reviewed
Open access
Abstract
A new method is introduced to construct approximations to Skyrmions that are explicit rational functions of the spatial Cartesian coordinates. The scheme uses ADHM data of a Yang–Mills ...instanton to produce a Skyrmion with a baryon number that is equal to the instanton number. The formula for the Skyrmion involves only the evaluation of the ADHM data, in contrast to the Atiyah–Manton construction that requires the solution of a differential equation that can only be solved explicitly in the case of a spherically symmetric Skyrmion. Examples with baryon numbers one and two are studied in detail. The energy of the rational Skyrmion with baryon number one is lower than that of the Atiyah–Manton Skyrmion, which is already within one percent of the energy of the true numerically computed Skyrmion. A family of baryon number two Skyrmions is presented, which includes an axially symmetric Skyrmion that smoothly transforms to a pair of well-separated single Skyrmions as the parameter is varied.
5-Fluorouracil (5-FU) is a chemotherapy used in colorectal, head and neck (H&N) and other cancers. Dose adjustment is based on body surface area (BSA) but wide variations occur. Pharmacokinetic (PK) ...dosing is suggested to bring plasma levels into the therapeutic range to promote fewer side effects and better patient outcomes. We investigated the clinical effectiveness and cost-effectiveness of the My5-FU assay for PK dose adjustment to 5-FU therapy.
To systematically review the evidence on the accuracy of the My5-FU assay compared with gold standard methods high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS); the effectiveness of My5-FU PK dosing compared with BSA; the effectiveness of HPLC and/or LC-MS compared with BSA; the generalisability of published My5-FU and PK studies; costs of using My5-FU; to develop a cost-effectiveness model.
We searched MEDLINE, EMBASE, Science Citation Index and other databases between January and April 2014.
Two reviewers independently screened titles and abstracts with arbitration and consensus agreement. We undertook quality assessment. We reconstructed Kaplan-Meier plots for progression-free survival (PFS) and overall survival (OS) for comparison of BSA and PK dosing. We developed a Markov model to compare My5-FU with BSA dosing which modelled PFS, OS and adverse events, using a 2-week cycle over a 20 year time horizon with a 3.5% discount rate. Health impacts were evaluated from the patient perspective, while costs were evaluated from the NHS and Personal Social Services perspective.
A total of 8341 records were identified through electronic searches and 35 and 54 studies were included in the clinical effectiveness and cost-effectiveness reviews respectively. There was a high apparent correlation between My5-FU, HPLC and LC-MS/mass spectrometer but upper and lower limits of agreement were -18% to 30%. Median OS were estimated as 19.6 95% confidence interval (CI) 17.0 to 21.0 months for PK versus 14.6 (95% CI 14.1 to 15.3) months for BSA for 5-FU+folinic acid (FA); and 27.4 (95% CI 23.2 to 38.8) months for PK versus 20.6 (95% CI 18.4 to 22.9) months for BSA for FOLFOX6 in metastatic colorectal cancer (mCRC). PK versus BSA studies were generalisable to the relevant populations. We developed cost-effectiveness models for mCRC and H&N cancer. The base case assumed a cost per My5-FU assay of £ 61.03. For mCRC for 12 cycles of a oxaliplatin in combination with 5-fluorouracil and FA (FOLFOX) regimen, there was a quality-adjusted life-year (QALY) gain of 0.599 with an incremental cost-effectiveness ratio of £ 4148 per QALY. Probabilistic and scenario analyses gave similar results. The cost-effectiveness acceptability curve showed My5-FU to be 100% cost-effective at a threshold of £ 20,000 per QALY. For H&N cancer, again, given caveats about the poor evidence base, we also estimated that My5-FU is likely to be cost-effective at a threshold of £ 20,000 per QALY.
Quality and quantity of evidence were very weak for PK versus BSA dosing for all cancers with no randomised controlled trials (RCTs) using current regimens. For H&N cancer, two studies of regimens no longer in use were identified.
Using a linked evidence approach, My5-FU appears to be cost-effective at a willingness to pay of £ 20,000 per QALY for both mCRC and H&N cancer. Considerable uncertainties remain about evidence quality and practical implementation. RCTs are needed of PK versus BSA dosing in relevant cancers.
An extension of the Skyrme model is presented in which derivative terms are added that break chiral symmetry to isospin symmetry. The theory contains just one new parameter and it reduces to the ...standard Skyrme model when this symmetry breaking parameter vanishes. The same Faddeev-Bogomolny energy bound applies for all parameter values, but the parameter can be tuned so that the energy of the single Skyrmion is much closer to the bound than in the standard Skyrme model. Applying the rational map approximation to multi-Skyrmions suggests that, for a suitable value of the symmetry breaking parameter, binding energies in this theory may be significantly more realistic than in the standard Skyrme model.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) (Zopf 1883) Lehmann and Neumann 1896, is a major cause of morbidity and mortality. Nearly one-third of the world's population is infected ...with MTB; TB has an annual incidence of 9 million new cases and each year causes 2 million deaths worldwide.
To investigate the clinical effectiveness and cost-effectiveness of screening tests interferon-gamma release assays (IGRAs) and tuberculin skin tests (TSTs) in latent tuberculosis infection (LTBI) diagnosis to support National Institute for Health and Care Excellence (NICE) guideline development for three population groups: children, immunocompromised people and those who have recently arrived in the UK from high-incidence countries. All of these groups are at higher risk of progression from LTBI to active TB.
Electronic databases including MEDLINE, EMBASE, The Cochrane Library and Current Controlled Trials were searched from December 2009 up to December 2014.
English-language studies evaluating the comparative effectiveness of commercially available tests used for identifying LTBI in children, immunocompromised people and recent arrivals to the UK were eligible. Interventions were IGRAs QuantiFERON(®)-TB Gold (QFT-G), QuantiFERON(®)-TB Gold-In-Tube (QFT-GIT) (Cellestis/Qiagen, Carnegie, VA, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK). The comparator was TST 5 mm or 10 mm alone or with an IGRA. Two independent reviewers screened all identified records and undertook a quality assessment and data synthesis. A de novo model, structured in two stages, was developed to compare the cost-effectiveness of diagnostic strategies.
In total, 6687 records were screened, of which 53 unique studies were included (a further 37 studies were identified from a previous NICE guideline). The majority of the included studies compared the strength of association for the QFT-GIT/G IGRA with the TST (5 mm or 10 mm) in relation to the incidence of active TB or previous TB exposure. Ten studies reported evidence on decision-analytic models to determine the cost-effectiveness of IGRAs compared with the TST for LTBI diagnosis. In children, TST (≥ 5 mm) negative followed by QFT-GIT was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of £18,900 per quality-adjusted life-year (QALY) gained. In immunocompromised people, QFT-GIT negative followed by the TST (≥ 5 mm) was the most cost-effective strategy, with an ICER of approximately £18,700 per QALY gained. In those recently arrived from high TB incidence countries, the TST (≥ 5 mm) alone was less costly and more effective than TST (≥ 5 mm) positive followed by QFT-GIT or T-SPOT.TB or QFT-GIT alone.
The limitations and scarcity of the evidence, variation in the exposure-based definitions of LTBI and heterogeneity in IGRA performance relative to TST limit the applicability of the review findings.
Given the current evidence, TST (≥ 5 mm) negative followed by QFT-GIT for children, QFT-GIT negative followed by TST (≥ 5 mm) for the immunocompromised population and TST (≥ 5 mm) for recent arrivals were the most cost-effective strategies for diagnosing LTBI that progresses to active TB. These results should be interpreted with caution given the limitations identified. The evidence available is limited and more high-quality research in this area is needed including studies on the inconsistent performance of tests in high-compared with low-incidence TB settings; the prospective assessment of progression to active TB for those at high risk; the relative benefits of two-compared with one-step testing with different tests; and improved classification of people at high and low risk for LTBI.
This study is registered as PROSPERO CRD42014009033.
The National Institute for Health Research Health Technology Assessment programme.
Evolvements in the design, fixation methods, size, and bearing surface of implants for total hip replacement (THR) have led to a variety of options for healthcare professionals to consider. The need ...to determine the most optimal combinations of THR implant is warranted. This systematic review evaluated the clinical effectiveness of different types of THR used for the treatment of end stage arthritis of the hip.
A comprehensive literature search was undertaken in major health databases. Randomised controlled trials (RCTs) and systematic reviews published from 2008 onwards comparing different types of primary THR in patients with end stage arthritis of the hip were included.
Fourteen RCTs and five systematic reviews were included. Patients experienced significant post-THR improvements in Harris Hip scores, but this did not differ between impact types. There was a reduced risk of implant dislocation after receiving a larger femoral head size (36 mm vs. 28 mm; RR = 0.17, 95% CI: 0.04, 0.78) or cemented cup (vs. cementless cup; pooled odds ratio: 0.34, 95% CI: 0.13, 0.89). Recipients of cross-linked vs. conventional polyethylene cup liners experienced reduced femoral head penetration and revision. There was no impact of femoral stem fixation and cup shell design on implant survival rates. Evidence on mortality and complications (aseptic loosening, femoral fracture) was inconclusive.
The majority of evidence was inconclusive due to poor reporting, missing data, or uncertainty in treatment estimates. The findings warrant cautious interpretation given the risk of bias (blinding, attrition), methodological limitations (small sample size, low event counts, short follow-up), and poor reporting. Long-term pragmatic RCTs are needed to allow for more definitive conclusions. Authors are encouraged to specify the minimal clinically important difference and power calculation for their primary outcome(s) as well CONSORT, PRISMA and STROBE guidelines to ensure better reporting and more reliable production and assessment of evidence.
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Tyrosinemia type 1 (TYR1) is a rare autosomal recessive disorder of amino acid metabolism that is fatal without treatment. With medication (nitisinone) and dietary restrictions outcomes are improved. ...We conducted a systematic review to investigate if treatment with nitisinone following screening provides better long-term outcomes than treatment with nitisinone following symptomatic detection.
We searched Web of Science, Medline, Pre-Medline, and Embase up to 23rd September 2016 for journal articles comparing clinical outcomes of TYR1 patients receiving earlier versus later nitisinone treatment. Two reviewers independently screened titles and abstracts, assessed full texts, and appraised study quality. Data extraction was performed by a single reviewer and checked by a second.
We included seven articles out of 470 unique records identified by our search. The seven articles included four studies (three cohort studies and one cross-sectional study). Study sample sizes ranged from 17 to 148. There is consistent evidence that nitisinone is an effective treatment for TYR1, and some evidence that earlier treatment with nitisinone and dietary restrictions within the first one or 2 months of life is associated with reduced need for liver transplantation, lower rates of renal dysfunction, fewer neurological crises, and fewer, shorter hospital admissions compared to later treatment. However, study quality was moderate to weak, with high risk of confounding and applicability concerns to the screening context. We conducted post hoc analyses to address these issues. Results suggested an association between earlier treatment and fewer liver transplants (earlier treatment: 0% of 10-24 patients; later treatment: 25-60% of 4-15 patients), but no impact on neurological crises. We found no effect of treatment timing on mortality in either the primary or post hoc analyses. Post hoc analyses of other health-related outcomes were not possible because of sample size or reporting.
There is some evidence from observational studies that earlier treatment with nitisinone might be beneficial but this is subject to bias. The applicability of our findings to the screening context or clinical practice is limited as not all early-treated patients were identified by screening and late-treated groups included patients born prior to the availability of nitisinone.
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Systematic reviews and economic modelling of clinical effectiveness and cost-effectiveness of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors using LISA-TRACKER
...enzyme-linked immunosorbent assay (ELISA) kits (Theradiag, Marne La Vallee, France, or Alpha Laboratories, Heriot, UK), TNF-α-Blocker ELISA kits (Immundiagnostik AG, Bensheim, Germany) and Promonitor
ELISA kits (Proteomika, Progenika Biopharma, Bizkaia, Spain) versus standard care for Crohn's disease (CD).
Multiple electronic databases were searched from inception to December 2014 in order to identify primary studies and meta-analyses.
Patients with moderate to severe active CD treated with infliximab (IFX) (Remicade
, Merck Sharp & Dohme Ltd, Kenilworth, NJ, USA) or adalimumab (ADA) (Humira
, AbbVie Inc., North Chicago, IL, USA).
Monitoring of serum anti-TNF-α (IFX or ADA) and/or of anti-drug antibody levels using test assays with a test-treatment algorithm.
Standard care.
Any patient-related outcome, test agreement and cost-effectiveness estimates. The quality assessments used recognised checklists (Quality Assessment of Diagnostic Accuracy Studies-2, Cochrane, Philips and Consolidated Health Economic Evaluation Reporting Standards). Evidence was synthesised using narrative review and meta-analysis. A Markov model was built in TreeAge Pro 2013 (TreeAge Software, Inc., Williamstown, MA, USA). The model had a 4-week cycle and a 10-year time horizon, adopted a NHS and Personal Social Services perspective and used a linked evidence approach. Costs were adjusted to 2013/14 prices and discounted at 3.5%.
We included 68 out of 2434 and 4 out of 2466 studies for the clinical effectiveness and cost-effectiveness reviews, respectively. Twenty-three studies comparing test methods were identified. Evidence on test concordance was sparse and contradictory, offering scant data for a linked evidence approach. Three studies two randomised controlled trials (RCTs) and one retrospective observational study investigated outcomes following implementation of a test algorithm. None used the specified commercial ELISA immunoassay test kits. Neither of the two RCTs demonstrated clinical benefit of a test-treatment regimen. A meta-analysis of 31 studies to estimate test accuracy for predicting clinical status indicated that 20-30% of test results are likely to be inaccurate. The four cost-effectiveness studies suggested that testing results in small cost reductions. In the economic analysis the base-case analysis showed that standard practice (no testing/therapeutic monitoring with the intervention tests) was more costly and more effective than testing for IFX. Sensitivity and scenario analyses gave similar results. The probabilistic sensitivity analysis indicated a 92% likelihood that the 'no-testing' strategy was cost-effective at a willingness to pay of £20,000 per quality-adjusted life-year.
Rigorous systematic reviews were undertaken; however, the underlying evidence base was poor or lacking. There was uncertainty about a linked evidence approach and a lack of gold standard for assay comparison. The only comparative evidence available for economic evaluation was for assays other than the intervention assays.
Our finding that testing is not cost-effective for IFX should be viewed cautiously in view of the limited evidence. Clinicians should be mindful of variation in performance of different assays and of the absence of standardised approaches to patient assessment and treatment algorithms.
There is substantial variation in the underlying treatment pathways and uncertainty in the relative effectiveness of assay- and test-based treatment algorithms, which requires further investigation. There is very little research evidence on ADA or on drug monitoring in children with CD, and conclusions on cost-effectiveness could not be reached for these.
This study is registered as PROSPERO CRD42014015278.
The National Institute for Health Research Health Technology Assessment programme.
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