Use of NHS Digital datasets as trial data in the UK: a position paper

Background: Clinical trial teams increasingly want to make use of data from healthcare systems (“healthcare data”), particularly to enhance recruitment and follow-up of participants, to reduce time and cost, and to stop the duplication of effort. However, there is continued uncertainty of how regulators regard healthcare data used for trial purposes, in terms of provenance, quality and reliability. Objectives: There were two key objectives: First, to demonstrate the data integrity of two datasets held by NHS Digital (NHSD) that are most requested by trial teams; and second, to set out an approach by which any other healthcare systems datasets can be similarly evaluated. Method: The data lifecycles of the datasets were carefully documented, mapping the flow of data from the originating healthcare provider’s databases to NHSD warehouses and onwards to clinical trials teams. These were assessed for evidence of whether the datasets are accurate, reliable, complete, contemporaneous, and well-governed. Result: The assessment method was applied to (a) the Hospital Episode Statistics Admitted Patient Care (HES APC) dataset and (b) the Civil Registration of Deaths (CRD) dataset. This paper clearly demonstrates that their collection and management through NHSD systems ensure their integrity and reliability. The datasets are accurate representations of the data held by the originating providers (acute NHS trusts and local registrars). Conclusion: Based on these findings, the HES APC and CRD datasets satisfy the assessment criteria that demonstrate they are reliable transcribed copies of the original source data. Implications: First, these datasets can be used directly for clinical trial data, with trial teams focusing on the accuracy of algorithms and processes to identify particular outcomes rather than on the integrity of the data flow. Second, this assessment approach should be used to assess whether other healthcare systems datasets are ready to be used as transcribed copies of source data, and for data providers to take appropriate steps to redress this matter if they are not

A randomized phase II study of SM-88 plus methoxsalen, phenytoin, and sirolimus in patients with metastatic pancreatic cancer treated in the second line and beyond

BACKGROUND: This trial explores SM-88 used with methoxsalen, phenytoin, and sirolimus (MPS) in pretreated metastatic pancreatic ductal adenocarcinoma (mPDAC) METHODS: Forty-nine patients were randomized to daily 460 or 920 mg oral SM-88 with MPS (SM-88 Regimen). The primary endpoint was objective response rate (RECIST 1.1). RESULTS: Thirty-seven patients completed ≥ one cycle of SM-88 Regimen (response evaluable population). Disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) did not differ significantly between dose levels. Stable disease was achieved in 9/37 patients (DCR, 24.3%); there were no complete or partial responses. Quality-of-life (QOL) was maintained and trended in favor of 920 mg. SM-88 Regimen was well tolerated; a single patient (1/49) had related grade 3 and 4 adverse events, which later resolved. In the intention-to-treat population of 49 patients, the median overall survival (mOS) was 3.4 months (95% CI: 2.7-4.9 months). Those treated in the second line had an mOS of 8.1 months and a median PFS of 3.8 months. Survival was higher for patients with stable versus progressive disease (any line; mOS: 10.6 months vs. 3.9 months; p = 0.01). CONCLUSIONS: SM-88 Regimen has a favorable safety profile with encouraging QOL effects, disease control, and survival trends. This regimen should be explored in the second-line treatment of patients with mPDAC. CLINICALTRIALS: gov Identifier: NCT03512756

The DARS (Dopamine Augmented Rehabilitation in Stroke) trial: protocol for a randomised controlled trial of Co-careldopa treatment in addition to routine NHS occupational and physical therapy after stroke

Background: Stroke has a huge impact, leaving more than a third of affected people with lasting disability and rehabilitation remains a cornerstone treatment in the National Health Service (NHS). Recovery of mobility and arm function post-stroke occurs through re-learning to use the affected body parts and/or learning to compensate with the lesser affected side. Promising evidence suggests that the addition of Co-careldopa to physical therapy and occupational therapy may improve the recovery of arm and leg movement and lead to improved function. Methods/design: Dopamine Augmented Rehabilitation in Stroke (DARS) is a multi-centre double-blind, randomised, placebo, controlled clinical trial of Co-careldopa in addition to routine NHS occupational therapy and physical therapy as part of early stroke rehabilitation. Participants will be randomised on a 1:1 basis to either Co-careldopa or placebo. The primary objective of the trial is to determine whether the addition of six weeks of Co-careldopa treatment to rehabilitation therapy can improve the proportion of patients who can walk independently eight weeks post-randomisation. Discussion: The DARS trial will provide evidence as to whether Co-careldopa, in addition to routine NHS occupational and physical therapy, leads to a greater recovery of motor function, a reduction in carer dependency and advance rehabilitation treatments for people with stroke. Trial registration: ISRCTN99643613 assigned on 4 December 2009

Glaciovolcanic hydrothermal environments in Iceland and implications for their detection on Mars

Volcanism has been a dominant process on Mars, along with a pervasive global cryosphere. Therefore, the interaction between these two is considered likely. Terrestrial glaciovolcanism produces distinctive lithologies and alteration terrains, as well as hydrothermal environments that can be inhabited by microorganisms. Here, we provide a framework for identifying evidence of such glaciovolcanic environments during future Mars exploration, and provide a descriptive reference for active hydrothermal environments to be utilised for future astrobiological studies. Remote sensing data were combined with field observations and sample analysis that included X-ray diffraction, Raman spectroscopy, thin section petrography, scanning electron microscopy, electron dispersive spectrometer analysis, and dissolved water chemistry to characterise samples from two areas of basaltic glaciovolcanism: Askja and Kverkfjöll volcanoes in Iceland. The glaciovolcanic terrain between these volcanoes is characterised by subglacially-erupted fissure swarm ridges, which have since been modified by multiple glacial outburst floods. Active hydrothermal environments at Kverkfjöll include hot springs, anoxic pools, glacial meltwater lakes, and sulfur- and iron- depositing fumaroles, all situated within ice-bound geothermal fields. Temperatures range from 0 °C - 94.4 °C, and aqueous environments are acidic - neutral (pH 2 - 7.5) and sulfate-dominated. Mineralogy of sediments, mineral crusts, and secondary deposits within basalts suggest two types of hydrothermal alteration: a low-temperature ( 120 °C) assemblage signified by zeolite (heulandite) and quartz. These mineral assemblages are consistent with those identified at the Martian surface. In-situ and laboratory VNIR (440 – 1000 nm) reflectance spectra representative of Mars rover multispectral imaging show sediment spectral profiles to be influenced by Fe2 +/3 + - bearing minerals, regardless of their dominant bulk mineralogy. Characterising these terrestrial glaciovolcanic deposits can help identify similar processes on Mars, as well as identifying palaeoenvironments that may once have supported and preserved life

An Embodied Approach in a Cognitive Discipline

Academia can be an uncomfortable place to work. Academics are examples of professionals who have multiple stresses and pressures. Being an academic is often a fundamental part of someone’s identity. Academia can be a cerebral, critical, competitive and judgmental environment. This chapter draws from a study using creative research methods with academics who self-identified as having an embodied practice. There are different definitions of embodiment. I use embodiment to mean both a state of being and a process of learning about the self, and so embodied practices are ways of bringing conscious self-awareness to and about the body. The academics reflected on the meanings they attributed to these embodied practices, tensions with their embodied identity, and how they used them to impact on their wellbeing

First measurement of the Hubble Constant from a Dark Standard Siren using the Dark Energy Survey Galaxies and the LIGO/Virgo Binary–Black-hole Merger GW170814

International audienceWe present a multi-messenger measurement of the Hubble constant H 0 using the binary–black-hole merger GW170814 as a standard siren, combined with a photometric redshift catalog from the Dark Energy Survey (DES). The luminosity distance is obtained from the gravitational wave signal detected by the Laser Interferometer Gravitational-Wave Observatory (LIGO)/Virgo Collaboration (LVC) on 2017 August 14, and the redshift information is provided by the DES Year 3 data. Black hole mergers such as GW170814 are expected to lack bright electromagnetic emission to uniquely identify their host galaxies and build an object-by-object Hubble diagram. However, they are suitable for a statistical measurement, provided that a galaxy catalog of adequate depth and redshift completion is available. Here we present the first Hubble parameter measurement using a black hole merger. Our analysis results in , which is consistent with both SN Ia and cosmic microwave background measurements of the Hubble constant. The quoted 68% credible region comprises 60% of the uniform prior range [20, 140] km s−1 Mpc−1, and it depends on the assumed prior range. If we take a broader prior of [10, 220] km s−1 Mpc−1, we find (57% of the prior range). Although a weak constraint on the Hubble constant from a single event is expected using the dark siren method, a multifold increase in the LVC event rate is anticipated in the coming years and combinations of many sirens will lead to improved constraints on H 0

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior

A gravitational-wave standard siren measurement of the Hubble constant

The detection of GW170817 (ref. 1) heralds the age of gravitational-wave multi-messenger astronomy, with the observations of gravitational-wave and electromagnetic emission from the same transient source. On 17 August 2017 the network of Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)2 and Virgo3 detectors observed GW170817, a strong signal from the merger of a binary neutron-star system. Less than two seconds after the merger, a γ-ray burst event, GRB 170817A, was detected consistent with the LIGO–Virgo sky localization region4–6). The sky region was subsequently observed by optical astronomy facilities7, resulting in the identification of an optical transient signal within about 10 arcseconds of the galaxy NGC 4993 (refs 8–13). GW170817 can be used as a standard siren14–18, combining the distance inferred purely from the gravitational-wave signal with the recession velocity arising from the electromagnetic data to determine the Hubble constant. This quantity, representing the local expansion rate of the Universe, sets the overall scale of the Universe and is of fundamental importance to cosmology. Our measurements do not require any form of cosmic ‘distance ladder’19; the gravitational-wave analysis directly estimates the luminosity distance out to cosmological scales. Here we report H0 = kilometres per second per megaparsec, which is consistent with existing measurements20,21, while being completely independent of them