Improving Providers’ Survival Estimates and Selection of Prognosis- and Guidelines-Appropriate Radiotherapy Regimens for Patients with Symptomatic Bone Metastases: Development and Evaluation of the BMETS Model and Decision Support Platform

In the management of symptomatic bone metastases, selection of appropriate palliative radiotherapy (RT) regimens should be based on patient-specific characteristics including estimated survival time. Yet, provider predictions of patient survival are notoriously inaccurate. Moreover, available evidence- and consensus-based guidelines do not provide clear criteria for selecting between the range of palliative RT regimens available. In an effort to improve selection of prognosis- and guidelines-appropriate palliative bone treatments, we developed the Bone Metastases Ensemble Trees for Survival (BMETS) model. Built using an institutional database of 397 patients seen in consultation for symptomatic bone metastases, this machine-learning model estimates survival time following RT consultation using 27 prognostic covariates. Cross validations procedures revealed excellent discrimination for survival, and the BMETS outperformed validated, simpler statistical models, justifying its use in this population. To better characterize a component of decisional uncertainty faced by providers, we next sought to identify the prevalence of “complicated” symptomatic bone metastases across a breadth of possible operational definitions. Our efforts identified up to 96 possible definitions of “complicated” bone metastases, present in up to 67.1% of patients in our database. Given that such “complicated” lesions may have been excluded from clinical trials in this setting, these data highlight the difficulty faced by providers when attempting to select appropriate RT regimens using inadequately defined selection criteria. Informed by these insights, we developed the BMETS Decision Support Platform (BMETS-DSP). This provider-facing, web-based tool was created to (1) collect relevant patient-specific data, (2) display an individualized predicted survival curve as per the BMETS model, and (3) provide case-specific, evidence-based recommendations for treatment of symptomatic bone metastases. We then conducted a pilot assessment of the clinical utility of the BMETS-DSP. In this preliminary assessment, the BMETS-DSP significantly improved physician accuracy in estimating survival and increased prognostic confidence, likelihood of sharing prognosis, and use of prognosis-appropriate RT regimens in the care of case patients. Collectively, this research provides early justification for the use of a machine-learning survival model and resultant decisions support platform to guide individualized selection of palliative RT regimens for symptomatic bone metastases. These data support a multi-institutional, randomized trial of the BMETS-DSP

Social communication between virtual characters and children with autism

Children with ASD have difficulty with social communication, particularly joint attention. Interaction in a virtual environment (VE) may be a means for both understanding these difficulties and addressing them. It is first necessary to discover how this population interacts with virtual characters, and whether they can follow joint attention cues in a VE. This paper describes a study in which 32 children with ASD used the ECHOES VE to assist a virtual character in selecting objects by following the character’s gaze and/or pointing. Both accuracy and reaction time data suggest that children were able to successfully complete the task, and qualitative data further suggests that most children perceived the character as an intentional being with relevant, mutually directed behaviour

Blending human and artificial intelligence to support autistic children’s social communication skills

This paper examines the educational efficacy of a learning environment in which children diagnosed with Autism Spectrum Conditions (ASC) engage in social interactions with an artificially intelligent (AI) virtual agent and where a human practitioner acts in support of the interactions. A multi-site intervention study in schools across the UK was conducted with 29 children with ASC and learning difficulties, aged 4-14 years old. For reasons related to data completeness and amount of exposure to the AI environment, data for 15 children was included in the analysis. The analysis revealed a significant increase in the proportion of social responses made by ASC children to human practitioners. The number of initiations made to human practitioners and to the virtual agent by the ASC children also increased numerically over the course of the sessions. However, due to large individual differences within the ASC group, this did not reach significance. Although no evidence of transfer to the real-world post-test was shown, anecdotal evidence of classroom transfer was reported. The work presented in this paper offers an important contribution to the growing body of research in the context of AI technology design and use for autism intervention in real school contexts. Specifically, the work highlights key methodological challenges and opportunities in this area by leveraging interdisciplinary insights in a way that (i) bridges between educational interventions and intelligent technology design practices, (ii) considers the design of technology as well as the design of its use (context and procedures) on par with one another, and (iii) includes design contributions from different stakeholders, including children with and without ASC diagnosis, educational practitioners and researchers

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

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Acute toxicity outcomes and dosimetric implications from incidental irradiation of adjacent tissues in tangent field hypofractionated breast radiotherapy

PurposeAdjacent tissues-in-beam (TIB) may receive substantial incidental doses within standard tangent fields during hypofractioned whole breast irradiation (HF-WBI). To characterize the impact of dose to TIB, we analyzed dosimetric parameters of TIB and associated acute toxicity.Materials and MethodsPlans prescribed to 40.5 Gy/15 fractions from 4/2016-1/2018 were evaluated. Structures of interest were contoured: (1) TIB: all tissues encompassed by plan 30% isodose lines, (2) breast, (3) non-breast TIB (nTIB): TIB minus contoured breast. Volumes of TIB, breast, and nTIB receiving 100%–107% of prescription dose (V100-V107) were calculated. Twelve patient- and physician-reported acute toxicities were prospectively collected weekly. Correlations between volumetric and dosimetric parameters were assessed. Uni- and multivariable logistic regressions evaluated toxicity grade changes as a function of TIB, breast, and nTIB V100-V107 (in cm3).ResultsWe evaluated 137 plans. Breast volume was positively correlated with nTIB and nTIB V100 (rho = 0.52, rho = 0.30, respectively, both p  2 cm3 were noted in 14% of breast and 21% of nTIB volumes. On multivariable analyses, increasing breast and nTIB V100 significantly raised odds of grade 2+ dermatitis and burning/twinging pain, respectively; increasing nTIB V105 elevated odds of hyperpigmentation and burning pain; and increasing nTIB V107 raised odds of burning pain. Threshold volumes for >6-fold odds of developing burning pain were TIB V105 > 100 cm3 and V107 > 5 cm3.ConclusionsFor HF-WBI, doses to nTIB over the prescription predicted acute toxicities independent of breast doses. These data support inclusion of TIB as a region of interest in treatment planning and protocol desig

Are Hindfoot Procedures More Painful than Forefoot – A Prospective Cohort Study in Foot and Ankle Reconstructive Surgery?

Category: Other Introduction/Purpose: Several variables are thought to have an effect on the post-operative pain relief after reconstructive foot and ankle surgery. In the past decade, the role of regional nerve blocks in the management of post-operative pain has become established. The technique(s) of regional blocks varies between centers and the published literature on this subject is inconsistent. More recently, image guided regional nerve blocks for post-op pain relief in F&A surgery have gained popularity. Traditionally, hindfoot reconstructive procedures are deemed to be more painful than the surgery involving the rest of the foot. This prospective study was carried out to examine this question. Methods: 143 patients undergoing elective foot and ankle surgery were prospectively studied. In addition to the demographics, the details of the anaesthetic used were also recorded. 70 patients received peripheral nerve blockade with guidance either by a nerve stimulator or ultrasonography. The procedures were categorised into those belonging to the forefoot, midfoot, hindfoot or combined. The magnitude of pain was recorded immediately post-operatively, at 6 hours and at 24 hours after the surgery, using the visual analog scale (VAS, 0 as ‘no pain’ and 10 as ‘ the worst possible pain’). All adverse effects were recorded. The patients’ satisfaction at two weeks after surgery was also assessed. Kruskal-Wallis test was used to perform non-parametric analysis between the groups. For categorical data, Pearson’s Chi-square test was used. Significant difference was demonstrated by a p-value < 0.05. Results: There was no difference in post-operative, 6 hours or 24 hours VAS in the patients having the hindfoot surgery or those having surgery involving the rest of the foot. Although patients who underwent peripheral nerve block had a satisfactory initial pain relief, they experienced significantly more pain at 24 hours than those who did not have a block (Table 1). There was no significant difference in the hospital stay or patient satisfaction at two weeks. In total, 94% patients were satisfied with their anaesthetic and would not mind having it again. Conclusion: This study provides evidence that contrary to the popular belief, hindfoot surgery is not more painful than the surgery involving the rest of the foot. Our results showed that patients who received peripheral nerve block probably had rebound pain at 24 hours after the surgery. Further studies are needed to explore this relationship. The detailed information provided by this study about the mean (and SD) VAS at various time points after surgery can be used to predict post-operative pain based on various pre-operative surgical and anaesthetic parameters