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The Paleocene-Eocene Thermal Maximum (PETM, approx. 56 Ma) provides a test case for investigating how the Earth system responds to rapid greenhouse gas-driven warming. However, current rates of carbon emissions are approximately 10 Pg C yr−1, whereas those proposed for the PETM span orders of magnitude-from <1 Pg C yr−1 to greater than the anthropogenic rate. Emissions rate estimates for the PETM are hampered by uncertainty over the total mass of PETM carbon released as well as the PETM onset duration. Here, I review constraints on the onset duration of the carbon isotope excursion (CIE) that is characteristic of the event with a focus on carbon cycle model-based attempts that forgo the need for a traditional sedimentary age model. I also review and compare existing PETM carbon input scenarios employing the Earth system model cGENIE and suggest another possibility-that abrupt input of an isotopically depleted carbon source combined with elevated volcanic outgassing over a longer interval can together account for key features of the PETM CIE. This article is part of a discussion meeting issue 'Hyperthermals: rapid and extreme global warming in our geological past'.

Knowledge of the onset duration of the Paleocene-Eocene Thermal Maximum—the largest known greenhouse-gas-driven global warming event of the Cenozoic—is central to drawing inferences for future climate change. Single-foraminifera measurements of the associated carbon isotope excursion from Maud Rise (South Atlantic Ocean) are controversial, as they seem to indicate geologically instantaneous carbon release and anomalously long ocean mixing. Here, we fundamentally reinterpret this record and extract the likely PETM onset duration. First, we employ an Earth system model to illustrate how the response of ocean circulation to warming does not support the interpretation of instantaneous carbon release. Instead, we use a novel sediment-mixing model to show how changes in the relative population sizes of calcareous plankton, combined with sediment mixing, can explain the observations. Furthermore, for any plausible PETM onset duration and sampling methodology, we place a probability on not sampling an intermediate, syn-excursion isotopic value. Assuming mixed-layer carbonate production continued at Maud Rise, we deduce the PETM onset was likely <5 kyr. Single-foraminifera measurements of the PETM carbon isotope excursion from Maud Rise have been interpreted as indicating geologically instantaneous carbon release. Here, the authors explain these records using an Earth system model and a sediment-mixing model and extract the likely PETM onset duration.

A series of unusual, greenhouse-gas-induced warming events occurred in the Eocene. An isotope reconstruction of these hyperthermals indicates multiple events of a constant size and frequency, consistent with orbital forcing of the carbon cycle. The Early Eocene Climatic Optimum (53–50 million years ago) was preceded by approximately six million years of progressive global warming 1 . This warming was punctuated by a series of rapid hyperthermal warming events triggered by the release of greenhouse gases 1 , 2 , 3 , 4 , 5 , 6 , 7 . Over these six million years, the carbon isotope record suggests that the events became more frequent but smaller in magnitude 3 , 5 , 6 , 7 . This pattern has been suggested to reflect a thermodynamic threshold for carbon release that was more easily crossed as global temperature rose, combined with a decrease in the size of carbon reservoirs during extremely warm conditions 8 , 9 , 10 , 11 . Here we present a continuous, 4.25-million-year-long record of the stable isotope composition of carbonate sediments from the equatorial Atlantic, spanning the peak of early Eocene global warmth. A composite of this and pre-existing 7 , 12 records shows that the carbon isotope excursions that identify the hyperthermals exhibit continuity in magnitude and frequency throughout the approximately 10-million-year period covering the onset, peak and termination of the Early Eocene Climate Optimum. We suggest that the carbon cycle processes behind these events, excluding the largest event, the Palaeocene–Eocene Thermal Maximum (about 56 million years ago), were not exceptional. Instead, we argue that the hyperthermals may reflect orbital forcing of the carbon cycle analogous to the mechanisms proposed 13 , 14 to operate in the cooler Oligocene and Miocene.

Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy. We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0–1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652. Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3–7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81–92) in the adjuvant radiotherapy group versus 87% (82–93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65–1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]). Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity. New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.

The methane (CH4) cycle is a key component of the Earth system that links planetary climate, biological metabolism, and the global biogeochemical cycles of carbon, oxygen, sulfur, and hydrogen. However, currently lacking is a numerical model capable of simulating a diversity of environments in the ocean, where CH4 can be produced and destroyed, and with the flexibility to be able to explore not only relatively recent perturbations to Earth's CH4 cycle but also to probe CH4 cycling and associated climate impacts under the very low-O2 conditions characteristic of most of Earth's history and likely widespread on other Earth-like planets. Here, we present a refinement and expansion of the ocean–atmosphere CH4 cycle in the intermediate-complexity Earth system model cGENIE, including parameterized atmospheric O2–O3–CH4 photochemistry and schemes for microbial methanogenesis, aerobic methanotrophy, and anaerobic oxidation of methane (AOM). We describe the model framework, compare model parameterizations against modern observations, and illustrate the flexibility of the model through a series of example simulations. Though we make no attempt to rigorously tune default model parameters, we find that simulated atmospheric CH4 levels and marine dissolved CH4 distributions are generally in good agreement with empirical constraints for the modern and recent Earth. Finally, we illustrate the model's utility in understanding the time-dependent behavior of the CH4 cycle resulting from transient carbon injection into the atmosphere, and we present model ensembles that examine the effects of atmospheric pO2, oceanic dissolved SO42-, and the thermodynamics of microbial metabolism on steady-state atmospheric CH4 abundance. Future model developments will address the sources and sinks of CH4 associated with the terrestrial biosphere and marine CH4 gas hydrates, both of which will be essential for comprehensive treatment of Earth's CH4 cycle during geologically recent time periods.

Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy. In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov (NCT00110162). Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3·3–6·2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86·4% (95% CI 78·5–91·5) in the delayed therapy arm versus 91·2% (84·2–95·2) in the immediate therapy arm (log-rank p=0·047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0·55 (95% CI 0·30–1·00; p=0·050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm. Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options. Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia.

The preservation of calcium carbonate in marine sediments is central to controlling the alkalinity balance of the ocean and, hence, the ocean–atmosphere partitioning of CO2. To successfully address carbon cycle–climate dynamics on geologic (≫1 kyr) timescales, Earth system models then require an appropriate representation of the primary controls on CaCO3 preservation. At the same time, marine sedimentary carbonates represent a major archive of Earth history, as they have the potential to preserve how seawater chemistry, isotopic composition, and even properties of planktic and benthic ecosystems, change with time. However, changes in preservation and even chemical erosion of previously deposited CaCO3, along with the biogenic reworking of upper portions of sediments, whereby sediment particles are translocated both locally and nonlocally between different depths in the sediments, all act to distort the recorded signal. Numerical models can aid in recovering what the “true” environmental changes might have been, but only if they appropriately account for these processes.Building on a classical 1-D reaction-transport framework, we present a new diagenetic model – IMP (Implicit model of Multiple Particles (and diagenesis)) – that simulates biogeochemical transformations in carbonate-hosted proxy signals by allowing for populations of solid carbonate particles to possess different physicochemical characteristics such as isotopic value, solubility and particle size. The model also utilizes a variable transition matrix to implement different styles of bioturbation. We illustrate the utility of the model for deciphering past environmental changes using several hypothesized transitions of seawater proxies obscured by sediment mixing and chemical erosion. To facilitate the use of IMP, we provide the model in Fortran, MATLAB and Python versions. We described IMP with integration into Earth system models in mind, and we present the description of this coupling of IMP with the “cGENIE.muffin” model in a subsequent paper.

The TROG 96.01 trial assessed whether 3-month and 6-month short-term neoadjuvant androgen deprivation therapy (NADT) decreases clinical progression and mortality after radiotherapy for locally advanced prostate cancer. Here we report the 10-year results. Between June, 1996, and February, 2000, 818 men with T2b, T2c, T3, and T4 N0 M0 prostate cancers were randomly assigned to receive radiotherapy alone, 3 months of NADT plus radiotherapy, or 6 months of NADT plus radiotherapy. The radiotherapy dose for all groups was 66 Gy, delivered to the prostate and seminal vesicles (excluding pelvic nodes) in 33 fractions of 2 Gy per day (excluding weekends) over 6·5–7·0 weeks. NADT consisted of 3·6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day. NADT began 2 months before radiotherapy for the 3-month NADT group and 5 months before radiotherapy for the 6-month NADT group. Primary endpoints were prostate-cancer-specific mortality and all-cause mortality. Treatment allocation was open label and randomisation was done with a minimisation technique according to age, clinical stage, tumour grade, and initial prostate-specific antigen concentration (PSA). Analysis was by intention-to-treat. The trial has been closed to follow-up and all main endpoint analyses are completed. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. 802 men were eligible for analysis (270 in the radiotherapy alone group, 265 in the 3-month NADT group, and 267 in the 6-month NADT group) after a median follow-up of 10·6 years (IQR 6·9–11·6). Compared with radiotherapy alone, 3 months of NADT decreased the cumulative incidence of PSA progression (adjusted hazard ratio 0·72, 95% CI 0·57–0·90; p=0·003) and local progression (0·49, 0·33–0·73; p=0·0005), and improved event-free survival (0·63, 0·52–0·77; p<0·0001). 6 months of NADT further reduced PSA progression (0·57, 0·46–0·72; p<0·0001) and local progression (0·45, 0·30–0·66; p=0·0001), and led to a greater improvement in event-free survival (0·51, 0·42–0·61, p<0·0001), compared with radiotherapy alone. 3-month NADT had no effect on distant progression (0·89, 0·60–1·31; p=0·550), prostate cancer-specific mortality (0·86, 0·60–1·23; p=0·398), or all-cause mortality (0·84, 0·65–1·08; p=0·180), compared with radiotherapy alone. By contrast, 6-month NADT decreased distant progression (0·49, 0·31–0·76; p=0·001), prostate cancer-specific mortality (0·49, 0·32–0·74; p=0·0008), and all-cause mortality (0·63, 0·48–0·83; p=0·0008), compared with radiotherapy alone. Treatment-related morbidity was not increased with NADT within the first 5 years after randomisation. 6 months of neoadjuvant androgen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer, particularly in men without nodal metastases or pre-existing metabolic comorbidities that could be exacerbated by prolonged androgen deprivation. Australian Government National Health and Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough.

The decision as to whether or not a patient should receive radiation therapy as part of their cancer treatment is based on evidence‐based practice and on recommended international consensus treatment guidelines. However, the merit of involving the patients' individual preferences and values in the treatment decision is frequently overlooked. Here, we review the current literature pertaining to shared decision‐making (SDM) in the field of radiation oncology, including discussion of the patient's perception of radiation therapy as a treatment option and patient involvement in clinical trials. The merit of decision aids during the SDM process in radiation oncology is considered, as are patient preferences for active or passive involvement in decisions about their treatment. Clarity of terminology, a better understanding of effective strategies and increased resources will be needed to ensure SDM in radiation oncology becomes a reality. Radiation therapy is a form of cancer treatment recommended for approximately half of all cancer patients. The patient as a decision‐maker in radiation therapy is frequently overlooked. This review explores the patient perception of radiation therapy as a treatment option and the evidence for using aids in assisting patients to make a decision about their cancer care.

The response of the Earth system to greenhouse-gas-driven warming is of critical importance for the future trajectory of our planetary environment. Hyperthermal events – past climate transients with global-scale warming significantly above background climate variability – can provide insights into the nature and magnitude of these responses. The largest hyperthermal of the Cenozoic was the Paleocene–Eocene Thermal Maximum (PETM ∼ 56 Ma). Here we present new high-resolution bulk sediment stable isotope and major element data for the classic PETM section at Zumaia, Spain. With these data we provide a new detailed stratigraphic correlation to other key deep-ocean and terrestrial PETM reference sections. With this new correlation and age model we are able to demonstrate that detrital sediment accumulation rates within the Zumaia continental margin section increased more than 4-fold during the PETM, representing a radical change in regional hydrology that drove dramatic increases in terrestrial-to-marine sediment flux. Most remarkable is that detrital accumulation rates remain high throughout the body of the PETM, and even reach peak values during the recovery phase of the characteristic PETM carbon isotope excursion (CIE). Using a series of Earth system model inversions, driven by the new Zumaia carbon isotope record, we demonstrate that the silicate weathering feedback alone is insufficient to recover the PETM CIE, and that active organic carbon burial is required to match the observed dynamics of the CIE. Further, we demonstrate that the period of maximum organic carbon sequestration coincides with the peak in detrital accumulation rates observed at Zumaia. Based on these results, we hypothesise that orbital-scale variations in subtropical hydro-climates, and their subsequent impact on sediment dynamics, may contribute to the rapid climate and CIE recovery from peak-PETM conditions.