Prognostic risk modelling for patients undergoing major lower limb amputation: an analysis of the UK National Vascular Registry

Objective Major lower limb amputation is the highest risk lower limb procedure in vascular surgery. Despite this, few high quality studies have examined factors contributing to mortality. The aim was to identify independent risk factors for peri-operative morbidity and mortality and develop reliable models for estimating risk. Methods All patients undergoing lower limb amputation above the ankle entered into the UK National Vascular Registry (January 2014–December 2016) were included. Missing data were handled using multiple imputation. Models were developed to evaluate independent risk factors for mortality (the primary outcome) and morbidity using logistic regression, minimising the Bayesian information criterion to balance complexity and model fit. Ethical approval for the study was granted (Wales REC 3 ref:16/WA/0353). Results All 9549 above ankle joint amputations in the registry were included. Overall, 865 patients (9.1%) died before leaving hospital. Independent factors associated with mortality were emergency admission, bilateral operation, age, American Society of Anesthesiologists' grade, abnormal electrocardiogram, and increased white cell count or creatinine (p < .01 for all). Independent factors reducing mortality were transtibial operation, increased albumin or patient weight, and previous ipsilateral revascularisation procedures (p < .01 for all). A risk model incorporating these factors had good discrimination (C-statistic 0.79, 95% confidence interval 0.77–0.80) and excellent calibration. Morbidity rates were high, with 6.6%, 9.7%, and 4.3% of patients suffering cardiac, respiratory, and renal complications, respectively. The risk model was also predictive of morbidity outcomes (C-statistics 0.74, 0.69, and 0.74, respectively). Conclusion Morbidity and mortality after lower limb amputation are high in the UK. Some potentially modifiable factors for quality improvement initiatives have been identified and accurate predictive models that could assist patient counselling and decision making have been developed

Development of core outcome sets for people undergoing major lower limb amputation for complications of peripheral vascular disease

Objective Every year, thousands of patients with peripheral vascular disease undergo major lower limb amputation. Despite this, evidence for optimal management is weak. Core outcome sets capture consensus on the most important outcomes for a patient group to improve the consistency and quality of research. The aim was to define short and medium term core outcome sets for studies involving patients undergoing major lower limb amputation. Methods A systematic review of the literature and focus groups involving patients, carers, and healthcare professionals were used to derive a list of potential outcomes. Findings informed a three round online Delphi consensus process, where outcomes were rated for both short and medium term studies. The results of the Delphi process were discussed at a face to face consensus meeting, and recommendations were made for each core outcome set. Results A systematic review revealed 45 themes to cazrry forward to the consensus survey. These were supplemented by a further five from focus groups. The consensus survey received responses from 123 participants in round one, and 91 individuals completed all three rounds. In the final round, nine outcomes were rated as “core” for short term studies and a further nine for medium term studies. Wound infection and healing were rated as “core” for both short and medium term studies. Outcomes related to mortality, quality of life, communication, and additional healthcare needs were also rated as “core” for short term studies. In medium term studies, outcomes related to quality of life, mobility, and social integration/independence were rated as “core”. The face to face stakeholder meeting ratified inclusion of all outcomes from the Delphi and suggested that deterioration of the other leg and psychological morbidity should also be reported for both short and medium term studies. Conclusion Consensus was established on 11 core outcomes for short and medium term studies. It is recommended that all future studies involving patients undergoing major lower limb amputation should report these outcomes

Linking the functions of unrelated proteins using a novel directed evolution domain insertion method

We have successfully developed a new directed evolution method for generating integral protein fusions comprising of one domain inserted within another. Creating two connections between the insert and accepting parent domain can result in the inter-dependence of the separate protein activities, thus providing a general strategy for constructing molecular switches. Using an engineered transposon termed MuDel, contiguous trinucleotide sequences were removed at random positions from the bla gene encoding TEM-1 β-lactamase. The deleted trinucleotide sequence was then replaced by a DNA cassette encoding cytochrome b562 with differing linking sequences at each terminus and sampling all three reading frames. The result was a variety of chimeric genes encoding novel integral fusion proteins that retained TEM-1 activity. While most of the tolerated insertions were observed in loops, several also occurred close to the termini of α-helices and β-strands. Several variants conferred a switching phenotype on Escherichia coli, with bacterial tolerance to ampicillin being dependent on the presence of haem in the growth medium. The magnitude of the switching phenotype ranged from 4- to 128-fold depending on the insertion position within TEM-1 and the linker sequences that join the two domains

Crisis? What Crisis? The Normality of the Current Food Crisis

The 2005–8 food crisis was a shock to political elites, but in some respects the situation was normal. Food policies are failing to respond adequately to the squeeze on land, people, health and environment. Strong evidence of systems failure and stress, termed here New Fundamentals, ought to reframe twenty-first century food politics and effort. Yet so far, international discourse is too often narrow and technical. The paper suggests that 2005–8 reinforced how the dominant twentieth century productionist policy paradigm is running out of steam. This assumed that producing more food would resolve social problems. Yet distortions in markets, access and culture remain. At national and international levels of governance, despite realization of the enormity of the challenge ahead, there is still a belief in slow incremental change

Importance of non-CO2 emissions in carbon management

Background: GHG budgets highlight a need for urgency, yet analyses are often CO2-focused, with less attention paid to non-CO2. Results: In this paper, scenarios are used to explore non-CO2 drivers and barriers to their mitigation, drawing out implications for CO2 management. Results suggest that even optimistic technological and consumption-related developments lead to on-going increases in global N2O, largely to improve food security within a changing climate. This contrasts with existing analysis, where lower levels of N2O by 2050 are projected. Conclusions: As avoiding '2°C' limits the emissions budget, constraints on reducing non-CO2 add pressure to energy system decarbonization. Overlooking how a changing climate and rising consumption restricts efforts to curb non-CO2 will result in policies aiming to avoid 2°C falling short of the mark

Friend or foe? UK farmers' relationships with the weather

Climate change will exacerbate the future challenges posed to sustaining food security in the UK. More frequent and intense extreme weather events will impact upon the ability of British farm systems to maintain or increase levels of food production. However, in this cultural context, relatively little is known about farmers' relationship with ‘the weather’, formed from their daily experiences of it. This paper engages at the farm scale to explore farmers' information-seeking behaviour about the weather, which influences their current risk perceptions of extreme weather conditions, through exploration of their assemblages of meteorological and local knowledge. Views are collected using a broad-based quantitative scoping survey combined with in-depth qualitative research with farmers located in the Welsh Marches border region of England and Wales, UK. Findings demonstrate that different types of farmer-weather relationships can be recognised depending upon the way weather and climate information is sought and utilised. We present a typology of farmer-weather relationships, categorising farmers as: analysts; intuitives; fatalists; or disengagers; with regards to the way in which they seek and interpret weather and climate information. This typology may assist the formation of new weather and climate services through an improved understanding of how lay and scientific knowledges interact in practice

Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2):a multicentre observational cohort study

Background: Cerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack. Methods: Our observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316. Findings: Between Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0–20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1–5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27–10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29–0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53–0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60–0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07–0·43, p=0·0065; and 0·33, 0·14–0·51, p=0·00059, respectively). Interpretation: In patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation. Funding: The Stroke Association and the British Heart Foundation

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes