How is overall survival assessed in randomised clinical trials in cancer and are subsequent treatment lines considered? A systematic review

Background: Overall survival is the “gold standard” endpoint in cancer clinical trials. It plays a key role in determining the clinical- and cost-effectiveness of a new intervention and whether it is recommended for use in standard of care. The assessment of overall survival usually requires trial participants to be followed up for a long period of time. In this time, they may stop receiving the trial intervention and receive subsequent anti-cancer treatments, which also aim to extend survival, during trial follow-up. This can potentially change the interpretation of overall survival in the context of the clinical trial. This review aimed to determine how overall survival has been assessed in cancer clinical trials and whether subsequent anti-cancer treatments are considered. Methods: Two searches were conducted using MEDLINE within OVID© on the 9th of November 2021. The first sought to identify papers publishing overall survival results from randomised controlled trials in eight reputable journals and the second to identify papers mentioning or considering subsequent treatments. Papers published since 2010 were included if presenting or discussing overall survival in the context of treating cancer. Results: One hundred and thirty-four papers were included. The majority of these were presenting clinical trial results (98, 73%). Of these, 45 (46%) reported overall survival as a (co-) primary endpoint. A lower proportion of papers including overall survival as a (co-) primary endpoint compared to a secondary endpoint were published in recent years. The primary analysis of overall survival varied across the papers. Fifty-nine (60%) mentioned subsequent treatments. Seven papers performed additional analysis, primarily when patients in the control arm received the experimental treatment during trial follow-up (treatment switching). Discussion: Overall survival has steadily moved from being the primary to a secondary endpoint. However, it is still of interest with papers presenting overall survival results with the caveat of subsequent treatments, but little or no investigation into their effect. This review shows that there is a methodological gap for what researchers should do when trial participants receive anti-cancer treatment during trial follow-up. Future research will identify the stakeholder opinions, on how this methodological gap should be addressed

Establishing comprehensive oral assessments for children with safeguarding concerns.

The dental profession is well placed to contribute important information in child protection cases but no previous research has been reported that assesses the volume or impact of this information. Comprehensive oral assessment clinics were introduced and established as an integral part of comprehensive medical assessments for children with welfare concerns in Greater Glasgow and Clyde. An assessment protocol and standardised paperwork for comprehensive oral assessments were developed to enhance information sharing and patient access to appropriate care. Two cases are presented and discussed to demonstrate the value of dental input

The development and validation of prognostic models for overall survival in the presence of missing data in the training dataset: a strategy with a detailed example.

Background The United Kingdom Myeloma Research Alliance (UK-MRA) Myeloma Risk Profile is a prognostic model for overall survival. It was trained and tested on clinical trial data, aiming to improve the stratification of transplant ineligible (TNE) patients with newly diagnosed multiple myeloma. Missing data is a common problem which affects the development and validation of prognostic models, where decisions on how to address missingness have implications on the choice of methodology. Methods Model building The training and test datasets were the TNE pathways from two large randomised multicentre, phase III clinical trials. Potential prognostic factors were identified by expert opinion. Missing data in the training dataset was imputed using multiple imputation by chained equations. Univariate analysis fitted Cox proportional hazards models in each imputed dataset with the estimates combined by Rubin’s rules. Multivariable analysis applied penalised Cox regression models, with a fixed penalty term across the imputed datasets. The estimates from each imputed dataset and bootstrap standard errors were combined by Rubin’s rules to define the prognostic model. Model assessment Calibration was assessed by visualising the observed and predicted probabilities across the imputed datasets. Discrimination was assessed by combining the prognostic separation D-statistic from each imputed dataset by Rubin’s rules. Model validation The D-statistic was applied in a bootstrap internal validation process in the training dataset and an external validation process in the test dataset, where acceptable performance was pre-specified. Development of risk groups Risk groups were defined using the tertiles of the combined prognostic index, obtained by combining the prognostic index from each imputed dataset by Rubin’s rules. Results The training dataset included 1852 patients, 1268 (68.47%) with complete case data. Ten imputed datasets were generated. Five hundred twenty patients were included in the test dataset. The D-statistic for the prognostic model was 0.840 (95% CI 0.716–0.964) in the training dataset and 0.654 (95% CI 0.497–0.811) in the test dataset and the corrected D-Statistic was 0.801. Conclusion The decision to impute missing covariate data in the training dataset influenced the methods implemented to train and test the model. To extend current literature and aid future researchers, we have presented a detailed example of one approach. Whilst our example is not without limitations, a benefit is that all of the patient information available in the training dataset was utilised to develop the model. Trial registration Both trials were registered; Myeloma IX-ISRCTN68454111, registered 21 September 2000. Myeloma XI-ISRCTN49407852, registered 24 June 2009

Aerosol Retrievals from Different Polarimeters During the ACEPOL Campaign Using a Common Retrieval Algorithm

In this paper, we present aerosol retrieval results from the ACEPOL (Aerosol Characterization from Polarimeter and Lidar) campaign, which was a joint initiative between NASA and SRON the Netherlands Institute for Space Research. The campaign took place in OctoberNovember 2017 over the western part of the United States. During ACEPOL six different instruments were deployed on the NASA ER-2 high-altitude aircraft, including four multi-angle polarimeters (MAPs): SPEX airborne, the Airborne Hyper Angular Rainbow Polarimeter (AirHARP), the Airborne Multi-angle SpectroPolarimetric Imager (AirMSPI), and the Research Scanning Polarimeter (RSP). Also, two lidars participated: the High Spectral Resolution Lidar-2 (HSRL-2) and the Cloud Physics Lidar (CPL). Flights were conducted mainly for scenes with low aerosol load over land, but some cases with higher AOD were also observed. We perform aerosol retrievals from SPEX airborne, RSP (410865 nm range only), and AirMSPI using the SRON aerosol retrieval algorithm and compare the results against AERONET (AErosol RObotic NETwork) and HSRL-2 measurements (for SPEX airborne and RSP). All three MAPs compare well against AERONET for the aerosol optical depth (AOD), with a mean absolute error (MAE) between 0.014 and 0.024 at 440 nm. For the fine-mode effective radius the MAE ranges between 0.021 and 0.028 m. For the comparison with HSRL-2 we focus on a day with low AOD (0.020.14 at 532 nm) over the California Central Valley, Arizona, and Nevada (26 October) as well as a flight with high AOD (including measurements with AOD>1.0 at 532 nm) over a prescribed forest fire in Arizona (9 November). For the day with low AOD the MAEs in AOD (at 532 nm) with HSRL-2 are 0.014 and 0.022 for SPEX and RSP, respectively, showing the capability of MAPs to provide accurate AOD retrievals for the challenging case of low AOD over land. For the retrievals over the smoke plume a reasonable agreement in AOD between the MAPs and HSRL-2 was also found (MAE 0.088 and 0.079 for SPEX and RSP, respectively), despite the fact that the comparison is hampered by large spatial variability in AOD throughout the smoke plume. A good comparison is also found between the MAPs and HSRL-2 for the aerosol depolarization ratio (a measure of particle sphericity), with an MAE of 0.023 and 0.016 for SPEX and RSP, respectively. Finally, SPEX and RSP agree very well for the retrieved microphysical and optical properties of the smoke plume

Non-Fermi liquid behavior below the Néel temperature in the frustrated heavy fermion magnet UAu₂

The term Fermi liquid is almost synonymous with the metallic state. The association is known to break down at quantum critical points (QCPs), but these require precise values of tuning parameters, such as pressure and applied magnetic field, to exactly suppress a continuous phase transition temperature to the absolute zero. Three-dimensional non-Fermi liquid states, apart from superconductivity, that are unshackled from a QCP are much rarer and are not currently well understood. Here, we report that the triangular lattice system uranium diauride (UAu2) forms such a state with a non-Fermi liquid low-temperature heat capacity [Formula: see text] and electrical resistivity [Formula: see text] far below its Néel temperature. The magnetic order itself has a novel structure and is accompanied by weak charge modulation that is not simply due to magnetostriction. The charge modulation continues to grow in amplitude with decreasing temperature, suggesting that charge degrees of freedom play an important role in the non-Fermi liquid behavior. In contrast with QCPs, the heat capacity and resistivity we find are unusually resilient in magnetic field. Our results suggest that a combination of magnetic frustration and Kondo physics may result in the emergence of this novel state

Architecture of the chromatin remodeler RSC and insights into its nucleosome engagement.

Eukaryotic DNA is packaged into nucleosome arrays, which are repositioned by chromatin remodeling complexes to control DNA accessibility. The Saccharomyces cerevisiae RSC (Remodeling the Structure of Chromatin) complex, a member of the SWI/SNF chromatin remodeler family, plays critical roles in genome maintenance, transcription, and DNA repair. Here, we report cryo-electron microscopy (cryo-EM) and crosslinking mass spectrometry (CLMS) studies of yeast RSC complex and show that RSC is composed of a rigid tripartite core and two flexible lobes. The core structure is scaffolded by an asymmetric Rsc8 dimer and built with the evolutionarily conserved subunits Sfh1, Rsc6, Rsc9 and Sth1. The flexible ATPase lobe, composed of helicase subunit Sth1, Arp7, Arp9 and Rtt102, is anchored to this core by the N-terminus of Sth1. Our cryo-EM analysis of RSC bound to a nucleosome core particle shows that in addition to the expected nucleosome-Sth1 interactions, RSC engages histones and nucleosomal DNA through one arm of the core structure, composed of the Rsc8 SWIRM domains, Sfh1 and Npl6. Our findings provide structural insights into the conserved assembly process for all members of the SWI/SNF family of remodelers, and illustrate how RSC selects, engages, and remodels nucleosomes

The future for diagnostic tests of acute kidney injury in critical care: evidence synthesis, care pathway analysis and research prioritisation

Background: Acute kidney injury (AKI) is highly prevalent in hospital inpatient populations, leading to significant mortality and morbidity, reduced quality of life and high short- and long-term health-care costs for the NHS. New diagnostic tests may offer an earlier diagnosis or improved care, but evidence of benefit to patients and of value to the NHS is required before national adoption. Objectives: To evaluate the potential for AKI in vitro diagnostic tests to enhance the NHS care of patients admitted to the intensive care unit (ICU) and identify an efficient supporting research strategy. Data sources: We searched ClinicalTrials.gov, The Cochrane Library databases, Embase, Health Management Information Consortium, International Clinical Trials Registry Platform, MEDLINE, metaRegister of Current Controlled Trials, PubMed and Web of Science databases from their inception dates until September 2014 (review 1), November 2015 (review 2) and July 2015 (economic model). Details of databases used for each review and coverage dates are listed in the main report. Review methods: The AKI-Diagnostics project included horizon scanning, systematic reviewing, meta-analysis of sensitivity and specificity, appraisal of analytical validity, care pathway analysis, model-based lifetime economic evaluation from a UK NHS perspective and value of information (VOI) analysis. Results: The horizon-scanning search identified 152 potential tests and biomarkers. Three tests, Nephrocheck® (Astute Medical, Inc., San Diego, CA, USA), NGAL and cystatin C, were subjected to detailed review. The meta-analysis was limited by variable reporting standards, study quality and heterogeneity, but sensitivity was between 0.54 and 0.92 and specificity was between 0.49 and 0.95 depending on the test. A bespoke critical appraisal framework demonstrated that analytical validity was also poorly reported in many instances. In the economic model the incremental cost-effectiveness ratios ranged from £11,476 to £19,324 per quality-adjusted life-year (QALY), with a probability of cost-effectiveness between 48% and 54% when tests were compared with current standard care. Limitations: The major limitation in the evidence on tests was the heterogeneity between studies in the definitions of AKI and the timing of testing. Conclusions: Diagnostic tests for AKI in the ICU offer the potential to improve patient care and add value to the NHS, but cost-effectiveness remains highly uncertain. Further research should focus on the mechanisms by which a new test might change current care processes in the ICU and the subsequent cost and QALY implications. The VOI analysis suggested that further observational research to better define the prevalence of AKI developing in the ICU would be worthwhile. A formal randomised controlled trial of biomarker use linked to a standardised AKI care pathway is necessary to provide definitive evidence on whether or not adoption of tests by the NHS would be of value. Study registration: The systematic review within this study is registered as PROSPERO CRD42014013919. Funding: The National Institute for Health Research Health Technology Assessment programme

Independent external validation of the QRISK3 cardiovascular disease risk prediction model using UK Biobank

Objective To externally evaluate the performance of QRISK3 for predicting 10 year risk of cardiovascular disease (CVD) in the UK Biobank cohort. Methods We used data from the UK Biobank, a large-scale prospective cohort study of 403 370 participants aged 40–69 years recruited between 2006 and 2010 in the UK. We included participants with no previous history of CVD or statin treatment and defined the outcome to be the first occurrence of coronary heart disease, ischaemic stroke or transient ischaemic attack, derived from linked hospital inpatient records and death registrations. Results Our study population included 233 233 women and 170 137 men, with 9295 and 13 028 incident CVD events, respectively. Overall, QRISK3 had moderate discrimination for UK Biobank participants (Harrell’s C-statistic 0.722 in women and 0.697 in men) and discrimination declined by age (<0.62 in all participants aged 65 years or older). QRISK3 systematically overpredicted CVD risk in UK Biobank, particularly in older participants, by as much as 20%. Conclusions QRISK3 had moderate overall discrimination in UK Biobank, which was best in younger participants. The observed CVD risk for UK Biobank participants was lower than that predicted by QRISK3, particularly for older participants. It may be necessary to recalibrate QRISK3 or use an alternate model in studies that require accurate CVD risk prediction in UK Biobank

From Offshore to Onshore: Multiple Origins of Shallow-Water Corals from Deep-Sea Ancestors

Shallow-water tropical reefs and the deep sea represent the two most diverse marine environments. Understanding the origin and diversification of this biodiversity is a major quest in ecology and evolution. The most prominent and well-supported explanation, articulated since the first explorations of the deep sea, holds that benthic marine fauna originated in shallow, onshore environments, and diversified into deeper waters. In contrast, evidence that groups of marine organisms originated in the deep sea is limited, and the possibility that deep-water taxa have contributed to the formation of shallow-water communities remains untested with phylogenetic methods. Here we show that stylasterid corals (Cnidaria: Hydrozoa: Stylasteridae)—the second most diverse group of hard corals—originated and diversified extensively in the deep sea, and subsequently invaded shallow waters. Our phylogenetic results show that deep-water stylasterid corals have invaded the shallow-water tropics three times, with one additional invasion of the shallow-water temperate zone. Our results also show that anti-predatory innovations arose in the deep sea, but were not involved in the shallow-water invasions. These findings are the first robust evidence that an important group of tropical shallow-water marine animals evolved from deep-water ancestors