Estimating the level of alpha heating and determining the onset of the burning plasma regime is essential to finding the path towards thermonuclear ignition. In a burning plasma, the alpha heating ...exceeds the external input energy to the plasma. Using a simple model of the implosion, it is shown that a general relation can be derived, connecting the burning plasma regime to the yield enhancement due to alpha heating and to experimentally measurable parameters such as the Lawson ignition parameter. A general alpha-heating curve is found, independent of the target and suitable to assess the performance of all laser fusion experiments whether direct or indirect drive. The onset of the burning plasma regime inside the hot spot of current implosions on the National Ignition Facility requires a fusion yield of about 50 kJ.
The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with ...salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression.
We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7–10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047.
Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60–68). Median follow-up was 4·9 years (IQR 3·0–6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81–1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58–1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3–4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020).
These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy.
Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.
In a series of wind-tunnel experiments conducted at the St. Anthony Falls Laboratory, a wind-turbine model was exposed to three different thermal regimes (neutral, weakly stable and weakly convective ...flows) in three simple arrangements relevant to wind-farm applications: single turbine in the boundary-layer, aligned turbine-turbine, and an upwind three-dimensional sinusoidal hill aligned with the turbine. Results focus on the spatial evolution of large-scale motions developing over the different thermal and topographic boundary conditions, and on their influence on the mean and fluctuating angular velocity of the turbine rotor. As compared to the single turbine case, both the upwind hill and turbine caused a reduction in the mean angular velocity regardless of the thermal regime; the turbine angular velocity fluctuations always decreased with a turbine upwind, which depleted the energy of the large structures of the flow; however such fluctuations decreased (increased) under stably stratified (convective) conditions when the hill was present. Pre-multiplied spectra of the rotor angular velocity and two-point correlation contours of the streamwise velocity component confirmed a non-trivial link between thermal stratification and terrain complexity. It is inferred that the thermal effects occurring in the three different boundary-layer regimes modulate the spanwise motion of the hill wake and define whether the hill shelters or exposes the turbine to enhanced large-scale energetic motions.
Advances in Virtual Reality (VR) technologies allow the investigation of simulated moral actions in visually immersive environments. Using a robotic manipulandum and an interactive sculpture, we now ...also incorporate realistic haptic feedback into virtual moral simulations. In two experiments, we found that participants responded with greater utilitarian actions in virtual and haptic environments when compared to traditional questionnaire assessments of moral judgments. In experiment one, when incorporating a robotic manipulandum, we found that the physical power of simulated utilitarian responses (calculated as the product of force and speed) was predicted by individual levels of psychopathy. In experiment two, which integrated an interactive and life-like sculpture of a human into a VR simulation, greater utilitarian actions continued to be observed. Together, these results support a disparity between simulated moral action and moral judgment. Overall this research combines state-of-the-art virtual reality, robotic movement simulations, and realistic human sculptures, to enhance moral paradigms that are often contextually impoverished. As such, this combination provides a better assessment of simulated moral action, and illustrates the embodied nature of morally-relevant actions.
High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in ...the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with
CDKN2A/B
homozygous deletion and/or
ATRX
mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (
n
= 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence
CDKN2A/B
homozygous deletion, and/or
ATRX
mutations/loss in this tumor type, along with a subset showing
NF1
alterations. Five of 93 (5.4%) cases sequenced harbored
TP53
mutations and RNA fusion analysis identified a single tumor containing an
NTRK2
gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (
n
= 18), g1 (
n
= 72), and g2 (
n
= 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%,
p
= 0.0008), confinement to the posterior fossa, hypermethylation in the
NF1
enhancer region, a trend towards decreased progression-free survival (
p
= 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (
p
< 0.0001 and
p
< 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.
Summary Background Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen ...could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. Methods In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 μg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov , number NCT00303784. Findings 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12–31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7–14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0–15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and −0·16 mmol/L (−2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and −0·23 mmol/L (−3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 19% of 78 patients in the LHRHa group vs 104 75% of 138 in the oestrogen-patch group), hot flushes (44 56% vs 35 25%), and dermatological problems (10 13% vs 58 42%). Interpretation Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. Funding Cancer Research UK, MRC Clinical Trials Unit.
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