Review and application of Rainflow residue processing techniques for accurate fatigue damage estimation

Most fatigue loaded structural components are subjected to variable amplitude loads which must be processed into a form that is compatible with design life calculations. Rainflow counting allows individual stress cycles to be identified where they form a closed stress-strain hysteresis loop within a random signal, but inevitably leaves a residue of open data points which must be post-processed. Comparison is made between conventional methods of processing the residue data points, which may be non-conservative, and a more versatile method, presented by Amzallag et al. (1994), which allows transition cycles to be processed accurately. This paper presents an analytical proof of the method presented by Amzallag et al. The impact of residue processing on fatigue calculations is demonstrated through the application and comparison of the different techniques in two case studies using long term, high resolution data sets. The most significance is found when the load process results in a slowly varying mean stress which is not fully accounted for by traditional Rainflow counting methods

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

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

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

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

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

A qualitative risk assessment for the impacts of climate change on nationally and internationally important geoheritage sites in Scotland

Climate change is a significant concern for nature conservation in the 21 st century. One of the goals of the 2014 Scottish Climate Change Adaptation Programme is to identify the consequences of climate change for protected areas and to put in place adaptation or mitigation measures. As a contribution to the process, this paper develops a methodology to identify the relative level of risk to nationally and internationally important geological and geomorphological sites in Scotland from the impacts of climate change. The methodology is based on existing understanding of the likely responses of different types of geosite to specific aspects of climate change, such as changes in rainfall, rising sea levels or increased storminess, and is applied to assess the likelihood of damaging impacts on groups of similar geoheritage features in sites with similar characteristics. The results indicate that 80 (8.8%) of the ∼900 nationally and internationally important geoheritage sites in Scotland are at ‘high’ risk from climate change. These include active soft-sediment coastal and fluvial features, finite Quaternary sediment exposures and landforms in coastal and river locations, active periglacial features, sites with palaeoenvironmental records, finite or restricted rock exposures and fossils. Using this risk-based assessment, development of indicative geoheritage climate-change actions have been prioritised for these sites. Depending on the characteristics of the sites, management options may range from ‘do nothing’ to rescue excavations and posterity recording. Monitoring is an essential part of the management process to trigger evidence-based interventions

A qualitative risk assessment for the impacts of climate change on nationally and internationally important geoheritage sites in Scotland

Climate change is a significant concern for nature conservation in the 21 st century. One of the goals of the 2014 Scottish Climate Change Adaptation Programme is to identify the consequences of climate change for protected areas and to put in place adaptation or mitigation measures. As a contribution to the process, this paper develops a methodology to identify the relative level of risk to nationally and internationally important geological and geomorphological sites in Scotland from the impacts of climate change. The methodology is based on existing understanding of the likely responses of different types of geosite to specific aspects of climate change, such as changes in rainfall, rising sea levels or increased storminess, and is applied to assess the likelihood of damaging impacts on groups of similar geoheritage features in sites with similar characteristics. The results indicate that 80 (8.8%) of the ∼900 nationally and internationally important geoheritage sites in Scotland are at ‘high’ risk from climate change. These include active soft-sediment coastal and fluvial features, finite Quaternary sediment exposures and landforms in coastal and river locations, active periglacial features, sites with palaeoenvironmental records, finite or restricted rock exposures and fossils. Using this risk-based assessment, development of indicative geoheritage climate-change actions have been prioritised for these sites. Depending on the characteristics of the sites, management options may range from ‘do nothing’ to rescue excavations and posterity recording. Monitoring is an essential part of the management process to trigger evidence-based interventions

Fluvio-marine sediment partitioning as a function of basin depth

Progradational fluvio-deltaic systems tend towards but cannot reach equilibrium, a state in which the longitudinal profile does not change shape and all sediment is bypassed beyond the shoreline. They cannot reach equilibrium because progradation of the shoreline requires aggradation along the longitudinal profile. Therefore progradation provides a negative feedback, unless relative sea level falls at a sufficient rate to cause non-aggradational extension of the longitudinal profile. How closely fluvio-deltaic systems approach equilibrium is dependent on their progradation rate, which is controlled by water depth and downstream allogenic controls, and governs sediment partitioning between the fluvial, deltaic, and marine domains. Here, six analogue models of coastal fluvio-deltaic systems and small prograding shelf margins are examined to better understand the effect of water depth, subsidence, and relative sea-level variations upon longitudinal patterns of sediment partitioning and grain-size distribution that eventually determine large-scale stratigraphic architecture. Fluvio-deltaic systems prograding in relatively deep-water environments are characterized by relatively low progradation rates compared to shallow-water systems. This allows these deeper water systems to approach equilibrium more closely, enabling them to construct less concave and steeper longitudinal profiles that provide low accommodation to fluvial systems. Glacio-eustatic sea-level variations and subsidence modulate the effects of water depth on the longitudinal profile. Systems are closest to equilibrium during falling relative sea level and early lowstand, resulting in efficient sediment transport towards the shoreline at those times. Additionally, the strength of the response to relative sea-level fall differs depending on water depth. In systems prograding into deep water, relative sea-level fall causes higher sediment bypass rates and generates significantly stronger erosion than in shallow-water systems, which increases the probability of incised-valley formation. Water depth in the receiving basin thus forms a first-order control on the sediment partitioning along the longitudinal profile of fluvio-deltaic systems and the shelf clinoform style. It also forms a control on the availability of sand-grade sediment at the shoreline that can potentially be remobilized and redistributed into deeper marine environments. Key findings are subsequently applied to the literature of selected shelf clinoform successions