Cancer‐associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in ...humans exposed to fluorouracil. Anti‐EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co‐administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta‐analysis of randomised, controlled trials assessing whether cancer patients receiving anti‐EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti‐cancer regimens with or without anti‐EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti‐EGFR monoclonal antibodies‐containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti‐EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non‐reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165.
What's new?
While monoclonal antibodies (MoAbs) targeting the epidermal growth factor receptor (EGFR) are effective anticancer agents, their use is associated with an increased risk of severe thromboembolism, a condition to which some cancer patients are predisposed. Nonetheless, the degree to which anti‐EGFR MoAbs contribute to this risk was unclear. In this systematic review of 17 different studies, thromboembolic events were found to be 1.5 times more likely in cancer patients treated with anti‐EGFR MoAb‐containing regimens than in patients given the same regimens but without MoAbs. Relative risk of thromboembolic events did not vary significantly between cancer types.
Marine litter is a growing concern for marine animals, including cetaceans for which there is a developing body of evidence showing impacts of both entanglement and ingestion. Better understanding is ...needed of the current and predicted scales of impacts on cetacean species of both macro- and micro-litter. Some emerging methodological approaches, such as the “threefold approach,” will help address data gaps. The relationship between this form of pollution and some cetaceans is strong and the particular feeding habits, and widespread distribution of two whale species means that they can be proposed as ocean health indicators for macro- and micro-litter impacts at global scales, helping steer research. The species concerned are sperm whales (
Physeter macrocephalus
), for macro-litter at depth, and fin whales (
Balaenoptera physalus
), for micro-debris. Once appropriate techniques have been fully developed for non-lethal assessment, other whale species might also be used as indicators of litter pollution in their specific feeding zones.
Abstract Background Prospective cohort studies have not been consistent in showing an association between serum homocysteine and dementia. Objective To conduct a meta-analysis of cohort studies that ...examined the relationship between serum homocysteine and dementia, and to estimate the change in risk of dementia for a unit change in serum homocysteine. Methods The data from eight cohort studies (involving 8669 participants; range of mean ages, 47–81 years; median duration of study, 5 years) of serum homocysteine on the incidence of dementia were combined and the odds ratio of dementia per 5 μmol/L increase in serum homocysteine was determined. Results There was a statistically significant association between serum homocysteine and the incidence of dementia: the odds ratio for a 5 μmol/L increase in serum homocysteine was 1.35 (95% confidence interval, 1.02–1.79) or 1.50 (1.13–2.00) adjusted for regression dilution bias. The odds ratio for a 3 μmol/L decrease in serum homocysteine (the average reduction expected using folic acid and B12) was 0.78 (0.66–0.93). Conclusion The meta-analysis of epidemiological cohort studies shows a positive association between serum homocysteine and dementia. Although the results do not provide evidence of cause and effect, they do provide an estimate of the expected effect if the relationship were causal; an approximate 20% reduction in risk of dementia from treatment with folic acid and B12.
Climate change is now known to be affecting the oceans. It is widely anticipated that impacts on marine mammals will be mediated primarily via changes in prey distribution and abundance and that the ...more mobile (or otherwise adaptable) species may be able to respond to this to some extent. However, the extent of this adaptability is largely unknown. Meanwhile, within the last few years direct observations have been made of several marine mammal populations that illustrate reactions to climate change. These observations indicate that certain species and populations may be especially vulnerable, including those with a limited habitat range, such as the vaquita Phocoena sinus, or those for which sea ice provides an important part of their habitat, such as narwhals Monodon monoceros, bowhead Balaena mysticetus and beluga Delphinapterus leucas whales and polar bears Ursus maritimus. Similarly, there are concerns about those species that migrate to feeding grounds in polar regions because of rapidly changing conditions there, and this includes many baleen whale populations. This review highlights the need to take projected impacts into account in future conservation and management plans, including species assessments. How this should be done in an adequately precautionary manner offers a significant challenge to those involved in such processes, although it is possible to identify at this time at least some species and populations that may be regarded as especially vulnerable. Marine ecosystems modellers and marine mammal experts will need to work together to make such assessments and conservation plans as robust as possible.
At least a quarter of the world's cetaceans were recently confirmed as endangered and the situation may be worse as the status of many others remains unclear. Climate change is affecting the oceans ...and a number of studies have recently highlighted its potential impact on cetacean species - for example, there are important linkages between sea ice and krill, the primary prey for baleen whales in Antarctica. This paper provides a synthesis of new information available on this theme and considers its implications for the future conservation and management of cetacean populations and species. The more mobile (or otherwise adaptable) cetaceans may be able to respond to climate related changes, although the extent of this adaptability is largely unknown. However, there is broad agreement that certain species and populations are likely to be especially vulnerable to climate related changes, including those with a limited habitat range, or those for which sea ice provides an important habitat for the cetacean population and/or that of their prey. International conservation bodies, such as the Convention for Migratory Species and the International Whaling Commission, are striving to address these issues. The challenges presented by climate change require an innovative, large scale, long term and multinational response from scientists, conservation managers and decision makers. This response that should encompass a precautionary approach, including addressing the detrimental effects of other factors negatively impacting populations and species.
Chronic heart failure is a debilitating condition that accounts for an annual NHS spend of £2.3B. Low levels of endogenous coenzyme Q10 may exacerbate chronic heart failure. Coenzyme Q10 supplements ...might improve symptoms and slow progression. As statins are thought to block the production of coenzyme Q10, supplementation might be particularly beneficial for patients taking statins.
To assess the clinical effectiveness and cost-effectiveness of coenzyme Q10 in managing chronic heart failure with a reduced ejection fraction.
A systematic review that included randomised trials comparing coenzyme Q10 plus standard care with standard care alone in chronic heart failure. Trials restricted to chronic heart failure with a preserved ejection fraction were excluded. Databases including MEDLINE, EMBASE and CENTRAL were searched up to March 2020. Risk of bias was assessed using the Cochrane Risk of Bias tool (version 5.2). A planned individual participant data meta-analysis was not possible and meta-analyses were mostly based on aggregate data from publications. Potential effect modification was examined using meta-regression. A Markov model used treatment effects from the meta-analysis and baseline mortality and hospitalisation from an observational UK cohort. Costs were evaluated from an NHS and Personal Social Services perspective and expressed in Great British pounds at a 2019/20 price base. Outcomes were expressed in quality-adjusted life-years. Both costs and outcomes were discounted at a 3.5% annual rate.
A total of 26 trials, comprising 2250 participants, were included in the systematic review. Many trials were reported poorly and were rated as having a high or unclear risk of bias in at least one domain. Meta-analysis suggested a possible benefit of coenzyme Q10 on all-cause mortality (seven trials, 1371 participants; relative risk 0.68, 95% confidence interval 0.45 to 1.03). The results for short-term functional outcomes were more modest or unclear. There was no indication of increased adverse events with coenzyme Q10. Meta-regression found no evidence of treatment interaction with statins. The base-case cost-effectiveness analysis produced incremental costs of £4878, incremental quality-adjusted life-years of 1.34 and an incremental cost-effectiveness ratio of £3650. Probabilistic sensitivity analyses showed that at thresholds of £20,000 and £30,000 per quality-adjusted life-year coenzyme Q10 had a high probability (95.2% and 95.8%, respectively) of being more cost-effective than standard care alone. Scenario analyses in which the population and other model assumptions were varied all found coenzyme Q10 to be cost-effective. The expected value of perfect information suggested that a new trial could be valuable.
For most outcomes, data were available from few trials and different trials contributed to different outcomes. There were concerns about risk of bias and whether or not the results from included trials were applicable to a typical UK population. A lack of individual participant data meant that planned detailed analyses of effect modifiers were not possible.
Available evidence suggested that, if prescribed, coenzyme Q10 has the potential to be clinically effective and cost-effective for heart failure with a reduced ejection fraction. However, given important concerns about risk of bias, plausibility of effect sizes and applicability of the evidence base, establishing whether or not coenzyme Q10 is genuinely effective in a typical UK population is important, particularly as coenzyme Q10 has not been subject to the scrutiny of drug-licensing processes. Stronger evidence is needed before considering its prescription in the NHS.
A new independent, well-designed clinical trial of coenzyme Q10 in a typical UK heart failure with a reduced ejection fraction population may be warranted.
This study is registered as PROSPERO CRD42018106189.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 26, No. 4. See the NIHR Journals Library website for further project information.
Background
Meta-analyses based on individual patient data (IPD) are regarded as the gold standard for systematic reviews. However, the methods used for analysing and presenting results from IPD ...meta-analyses have received little discussion.
Methods
We review 44 IPD meta-analyses published during the years 1999–2001. We summarize whether they obtained all the data they sought, what types of approaches were used in the analysis, including assumptions of common or random effects, and how they examined the effects of covariates.
Results
Twenty-four out of 44 analyses focused on time-to-event outcomes, and most analyses (28) estimated treatment effects within each trial and then combined the results assuming a common treatment effect across trials. Three analyses failed to stratify by trial, analysing the data is if they came from a single mega-trial. Only nine analyses used random effects methods. Covariate-treatment interactions were generally investigated by subgrouping patients. Seven of the meta-analyses included data from less than 80% of the randomized patients sought, but did not address the resulting potential biases.
Conclusions
Although IPD meta-analyses have many advantages in assessing the effects of health care, there are several aspects that could be further developed to make fuller use of the potential of these time-consuming projects. In particular, IPD could be used to more fully investigate the influence of covariates on heterogeneity of treatment effects, both within and between trials. The impact of heterogeneity, or use of random effects, are seldom discussed. There is thus considerable scope for enhancing the methods of analysis and presentation of IPD meta-analysis.
High-throughput non-invasive prenatal testing (NIPT) for fetal rhesus (D antigen) (RhD) status could avoid unnecessary treatment with routine anti-D immunoglobulin for RhD-negative women carrying a ...RhD-negative fetus, although this may lead to an increased risk of RhD sensitisations.
To systematically review the evidence on the diagnostic accuracy, clinical effectiveness and implementation of high-throughput NIPT and to develop a cost-effectiveness model.
We searched MEDLINE and other databases, from inception to February 2016, for studies of high-throughput NIPT free-cell fetal deoxyribonucleic acid (DNA) tests of maternal plasma to determine fetal RhD status in RhD-negative pregnant women who were not known to be sensitised to the RhD antigen. Study quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) and A Cochrane Risk of Bias Assessment Tool: for Non-Randomised Studies of Interventions (ACROBAT-NRSI). Summary estimates of false-positive rates (FPRs) and false-negative rates (FNRs) were calculated using bivariate models. Clinical effectiveness evidence was used to conduct a simulation study. We developed a de novo probabilistic decision tree-based cohort model that considered four alternative ways in which the results of NIPT could guide the use of anti-D immunoglobulin antenatally and post partum. Sensitivity analyses (SAs) were conducted to address key uncertainties and model assumptions.
Eight studies were included in the diagnostic accuracy review, seven studies were included in the clinical effectiveness review and 12 studies were included in the review of implementation. Meta-analyses included women mostly at or post 11 weeks' gestation. The pooled FNR (women at risk of sensitisation) was 0.34% 95% confidence interval (CI) 0.15% to 0.76% and the pooled FPR (women needlessly receiving anti-D) was 3.86% (95% CI 2.54% to 5.82%). SAs did not materially alter the overall results. Data on clinical outcomes, including sensitisation rates, were limited. Our simulation suggests that NIPT could substantially reduce unnecessary use of antenatal anti-D with only a small increase in the risk of sensitisation. All large implementation studies suggested that large-scale implementation of high-throughput NIPT was feasible. Seven cost-effectiveness studies were included in the review, which found that the potential for the use of NIPT to produce cost savings was dependent on the cost of the test. Our de novo model suggested that high-throughput NIPT is likely to be cost saving compared with the current practice of providing routine antenatal anti-D prophylaxis to all women who are RhD negative. The extent of the cost saving appeared to be sufficient to outweigh the small increase in sensitisations. However, the magnitude of the cost saving is highly sensitive to the cost of NIPT itself.
There was very limited evidence relating to the clinical effectiveness of high-throughput NIPT, with no evidence on potential adverse effects. The generalisability of the findings to non-white women and multiple pregnancies is unclear.
High-throughput NIPT is sufficiently accurate to detect fetal RhD status in RhD-negative women from 11 weeks' gestation and would considerably reduce unnecessary treatment with routine anti-D immunoglobulin, potentially resulting in cost savings of between £485,000 and £671,000 per 100,000 pregnancies if the cost of implementing NIPT is in line with that reflected in this evaluation.
Further research on the diagnostic accuracy of NIPT in non-white women is needed.
This study is registered as PROSPERO CRD42015029497.
The National Institute for Health Research Health Technology Assessment programme.
Marine renewable energy is seen as an important component of the UK's future energy strategy and contribution to reducing the greenhouse gas emissions responsible for climate change. The UK aims to ...generate a total of 33GW (gigawatts) of offshore wind energy. Its implementation strategy includes the development of ten offshore wind farms within Scottish territorial waters. In addition, between 1000MW (megawatts) and 2600MW of marine renewable energy generating capacity could be achieved in Scotland using wave and tidal power devices. However, there are negative environmental impacts associated with marine renewable energy. Intense noise is produced during pile driving, drilling and dredging operations with potential consequences for cetaceans. There are also increases in vessel activities during exploration, maintenance and construction with association risks of disturbance and collisions. Some underwater devices will be large and may be positioned in arrays across the habitats that cetaceans frequent. The consequences of encounters between cetaceans and such devices are as yet unknown. It is recommended that the Scottish Government complete full and transparent Marine Spatial Planning, including consideration of cumulative impacts, before moving to license appropriate sites.
Dynamic Spectral Imaging System (DySIS)map (DySIS Medical Ltd, Edinburgh, UK) and ZedScan (Zilico Limited, Manchester, UK) can be used adjunctively with conventional colposcopy, which may improve the ...detection of cervical intraepithelial neoplasia (CIN) and cancer.
To systematically review the evidence on the diagnostic accuracy, clinical effectiveness and implementation of DySISmap and ZedScan as adjuncts to standard colposcopy, and to develop a cost-effectiveness model.
Four parallel systematic reviews were performed on diagnostic accuracy, clinical effectiveness issues, implementation and economic analyses. In January 2017 we searched databases (including MEDLINE and EMBASE) for studies in which DySISmap or ZedScan was used adjunctively with standard colposcopy to detect CIN or cancer in women referred to colposcopy. Risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. Summary estimates of diagnostic accuracy were calculated using bivariate and other regression models when appropriate. Other outcomes were synthesised narratively. A patient-level state-transition model was developed to evaluate the cost-effectiveness of DySISmap and ZedScan under either human papillomavirus (HPV) triage or the HPV primary screening algorithm. The model included two types of clinics 'see and treat' and 'watchful waiting' (i.e. treat later after confirmatory biopsy), as well as the reason for referral (low-grade or high-grade cytological smear). Sensitivity and scenario analyses were undertaken.
Eleven studies were included in the diagnostic review (nine of DySISmap and two of ZedScan), three were included in the clinical effectiveness review (two of DySISmap and one of ZedScan) and five were included in the implementation review (four of DySISmap and one of ZedScan). Adjunctive DySISmap use was found to have a higher sensitivity for detecting CIN grade 2+ (CIN 2+) lesions 81.25%, 95% confidence interval (CI) 72.2% to 87.9% than standard colposcopy alone (57.91%, 95% CI 47.2% to 67.9%), but with a lower specificity (70.40%, 95% CI 59.4% to 79.5%) than colposcopy (87.41%, 95% CI 81.7% to 91.5%). (Confidential information has been removed.) The base-case cost-effectiveness results showed that adjunctive DySISmap routinely dominated standard colposcopy (it was less costly and more effective). The only exception was for high-grade referrals in a watchful-waiting clinic setting. The incremental cost-effectiveness ratio for ZedScan varied between £272 and £4922 per quality-adjusted life-year. ZedScan also dominated colposcopy alone for high-grade referrals in see-and-treat clinics. These findings appeared to be robust to a wide range of sensitivity and scenario analyses.
All but one study was rated as being at a high risk of bias. There was no evidence directly comparing ZedScan with standard colposcopy. No studies directly compared DySIS and ZedScan.
The use of adjunctive DySIS increases the sensitivity for detecting CIN 2+, so it increases the number of high-grade CIN cases that are detected. However, it also reduces specificity, so that more women with no or low-grade CIN will be incorrectly judged as possibly having high-grade CIN. The evidence for ZedScan was limited, but it appears to increase sensitivity and decrease specificity compared with colposcopy alone. The cost-effectiveness of both adjunctive technologies compared with standard colposcopy, under both the HPV triage and primary screening algorithms, appears to be favourable when compared with the conventional thresholds used to determine value in the NHS.
More diagnostic accuracy studies of ZedScan are needed, as are studies assessing the diagnostic accuracy for women referred to colposcopy as part of the HPV primary screening programme.
This study is registered as PROSPERO CRD42017054515.
The National Institute for Health Research Health Technology Assessment programme.
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