Experimental Temperature Analysis of Powder-Based Electron Beam Additive Manufacturing

A near infrared thermal imager has been employed for temperature measurements (build part surfaces) in the powder-based electron beam additive manufacturing (EBAM) process. A methodology has also been developed to analyze temperature distributions and history around the melting scan area. The temperature profiles along the beam scanning clearly show the moving source of heat phenomenon, with the peak temperature reaching over 2000 °C (for Ti6Al-4V) followed by extremely rapid cooling opposite to the beam scanning direction, except a slow-cooling portion corresponding to the liquidus-solidus range. The build surface temperatures and the melt pool sizes, in the localized electron beam scanning area, were studied at various configurations, e.g., different build heights, also with or without an overhang.Mechanical Engineerin

SHEPHERDING TALENT – AN INFORMAL FORMATION PROGRAMME FOR ASPIRING CATHOLIC SCHOOL LEADERS

Shepherding Talent is a pioneering informal formation programme in which teachers identified as having potential for leadership are challenged to explore their vocation to lead. The content of the programme is based around the imperative for all Catholic schools to maintain a balance between school improvement and Catholic distinctiveness. The integrity of vocation and profession in the context of discipleship figures prominently and defines the nature of the seminars. Through workshops, the mission of the Catholic educator is elucidated alongside a consideration of personal disposition and values, inviting a critically reflective response to leadership. This interplay and its impact will be discussed during the presentation and the next stages to more formal and lifelong opportunities for formation through the Master’s degree in Catholic School Leadership at St Mary’s University, Twickenham

Elevated antiphospholipid antibody titers and adverse pregnancy outcomes: analysis of a population-based hospital dataset

<p>Abstract</p> <p>Background</p> <p>The primary objective of this study was to determine if elevated antiphospholipid antibody titers were correlated with the presence of preeclampsia/eclampsia, systemic lupus erythematosus (SLE), placental insufficiency, and a prolonged length of stay (PLOS), in women who delivered throughout Florida, USA.</p> <p>Methods</p> <p>Cross-sectional analyses were conducted using a statewide hospital database. Prevalence odds ratios (OR) were calculated to quantify the association between elevated antiphospholipid antibody titers and four outcomes in 141,286 women who delivered in Florida in 2001. The possibility that the relationship between elevated antiphospholipid antibody titers and the outcomes of preeclampsia/eclampsia, placental insufficiency, and PLOS, may have been modified by the presence of SLE was evaluated in a multiple logistic regression model by creating a composite interaction term.</p> <p>Results</p> <p>Women with elevated antiphospholipid antibody titers (n = 88) were older, more likely to be of white race and not on Medicaid than women who did not have elevated antiphospholipid antibody titers. Women who had elevated antiphospholipid antibody titers had an increased adjusted odds ratio for preeclampsia and eclampsia, (OR = 2.93 p = 0.0015), SLE (OR = 61.24 p < 0.0001), placental insufficiency (OR = 4.58 p = 0.0003), and PLOS (OR = 3.93 p < 0.0001). Patients who had both an elevated antiphospholipid antibody titer and SLE were significantly more likely than the comparison group (women without an elevated titer who did not have SLE) to have the outcomes of preeclampsia, placental insufficiency and PLOS.</p> <p>Conclusion</p> <p>This exploratory epidemiologic investigation found moderate to very strong associations between elevated antiphospholipid antibody titers and four important outcomes in a large sample of women.</p

Human volunteer study of the decontamination of chemically contaminated hair and the consequences for systemic exposure

The decontamination of exposed persons is a priority following the release of toxic chemicals. Efficacious decontamination reduces the risk of harm to those directly affected and prevents the uncontrolled spread of contamination. Human studies examining the effectiveness of emergency decontamination procedures have primarily focused on decontaminating skin, with few examining the decontamination of hair and scalp. We report the outcome of two studies designed to evaluate the efficacy of current United Kingdom (UK) improvised, interim and specialist mass casualty decontamination protocols when conducted in sequence. Decontamination efficacy was evaluated using two chemical simulants, methyl salicylate (MeS) and benzyl salicylate (BeS) applied to and recovered from the hair of volunteers. Twenty-four-hour urinary MeS and BeS were measured as a surrogate for systemic bioavailability. Current UK decontamination methods performed in sequence were partially effective at removing MeS and BeS from hair and underlying scalp. BeS and MeS levels in urine indicated that decontamination had no significant effect on systemic exposure raising important considerations with respect to the speed of decontamination. The decontamination of hair may therefore be challenging for first responders, requiring careful management of exposed persons following decontamination. Further work to extend these studies is required with a broader range of chemical simulants, a larger group of volunteers and at different intervention times

TUXEDO: a phase I/II trial of cetuximab with chemoradiotherapy in muscle‐invasive bladder cancer.

Objective To assess the feasibility and preliminary efficacy of adding cetuximab to standard chemoradiotherapy for muscle-invasive bladder cancer. Patients and Methods TUXEDO was a prospective, single-arm, open-label, phase I/II trial conducted in six UK hospitals. Cetuximab was administered with an initial loading dose of 400 mg/m2 on Day 1 of Week −1, and then seven weekly doses of 250 mg/m2. The radiotherapy schedule was 64 Gy/32F with Day 1 mitomycin C (12 g/m2) and 5-fluorouracil (500 mg/m2/day) over Days 1–5 and Days 22–26. Patients with T2-4aN0M0 urothelial cancer and a performance status of 0–1 were eligible. Prior neoadjuvant therapy was permitted. The Phase I primary outcome was impact on radiotherapy treatment completion and toxicity experienced during treatment. The Phase II primary outcome was local control at 3 months post treatment. Results Between September 2012 and October 2016, 33 patients were recruited; seven in Phase I, 26 in Phase II. Three patients in Phase II were subsequently deemed ineligible and received no trial therapy. Eight patients discontinued cetuximab due to adverse effects. The patients’ median (range) age was 70.1 (60.6–75.1) years, 20 had a performance status of 0, 27 were male and 26 had already received neoadjuvant chemotherapy. In Phase I, all patients completed planned radiotherapy, with no delays or dose reductions. Of the 30 evaluable patients in Phase II, 25 had confirmed local control 3 months after treatment (77%, 95% confidence interval 58–90). During the trial there were 18 serious adverse events. The study was halted due to slow accrual. Conclusion Phase I data demonstrate it is feasible and safe to add cetuximab to chemoradiotherapy. Exploratory analysis of Phase II data provides evidence to consider further clinical evaluation of cetuximab in this setting

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial.

BACKGROUND: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). METHODS AND FINDINGS: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. CONCLUSIONS: Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544

Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer (PCa): Combined analysis from two comparisons in the STAMPEDE platform protocol

This is an accepted manuscript of an abstract published by Elsevier in Annals of Oncology on 01/09/2021, available online: https://doi.org/10.1016/j.annonc.2021.08.2098 The accepted version of the publication may differ from the final published version.Published versio

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer : long-term survival results from the STAMPEDE trial

Background STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. Methods We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. Results Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69–0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57–0.76, P  0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). Conclusions The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial

BACKGROUND: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). METHODS AND FINDINGS: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p &lt; 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p &lt; 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. CONCLUSIONS: Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol

BACKGROUND: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. METHODS: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544. FINDINGS: Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63-73) and median PSA 34 ng/ml (14·7-47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60-84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]-NE) than in the control groups (not reached, 97-NE; hazard ratio [HR] 0·53, 95% CI 0·44-0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79-85) in the combination-therapy group and 69% (66-72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70-1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached [IQR NE-NE] in the combination-therapy groups vs not reached [103-NE] in the control groups; HR 0·60, 95% CI 0·48-0·73, p<0·0001), prostate cancer-specific survival (not reached [NE-NE] vs not reached [NE-NE]; 0·49, 0·37-0·65, p<0·0001), biochemical failure-free-survival (not reached [NE-NE] vs 86 months [83-NE]; 0·39, 0·33-0·47, p<0·0001), and progression-free-survival (not reached [NE-NE] vs not reached [103-NE]; 0·44, 0·36-0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death). INTERPRETATION: Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas