Subversion of allocation concealment in a randomised controlled trial : a historical case study

BACKGROUND: If the randomisation process within a trial is subverted, this can lead to selection bias that may invalidate the trial's result. To avoid this problem, it is recommended that some form of concealment should be put into place. Despite ongoing anecdotal concerns about their susceptibility to subversion, a surprising number of trials (over 10%) still use sealed opaque envelopes as the randomisation method of choice. This is likely due in part to the paucity of empirical data quantifying the potential effects of subversion. In this study we report a historical before and after study that compares the use of the sealed envelope method with a more secure centralised telephone allocation approach in order to provide such empirical evidence of the effects of subversion. METHODS: This was an opportunistic before and after study set within a multi-centre surgical trial, which involved 654 patients from 28 clinicians from 23 centres in the UK and Ireland. Two methods of randomly allocating subjects to alternative treatments were adopted: (a) a sealed envelope system administered locally, and (b) a centralised telephone system administered by the trial co-ordination centre. Key prognostic variables were compared between randomisation methods: (a) age at trial entry, a key prognostic factor in the study, and (b) the order in which 'randomisation envelopes' were matched to subjects. RESULTS: The median age of patients allocated to the experimental group with the sealed envelope system, was significantly lower both overall (59 vs 63 years, p < 0.01) and in particular for three clinicians (57 vs 72, p < 0.01; 33 vs 69, p < 0.001; 47 vs 72, p = 0.03). No differences in median age were found between the allocation groups for the centralised system. CONCLUSIONS: Due to inadequate allocation concealment with the sealed envelope system, the randomisation process was corrupted for patients recruited from three clinicians. Centralised randomisation ensures that treatment allocation is not only secure but seen to be secure. Where this proves to be impossible, allocation should at least be performed by an independent third party. Unless it is an absolute requirement, the use of sealed envelopes should be discontinued forthwith

Thermal history recorded by the Apollo 17 impact melt breccia 73217

Lunar breccia 73217 is composed of plagioclase and pyroxene clasts originating from a single gabbronorite intrusion, mixed with a silica-rich glass interpreted to represent an impact melt. A study of accessory minerals in a thin section from this breccia (73217,52) identified three different types of zircon and anhedral grains of apatite which represent distinct generations of accessory phases and provide a unique opportunity to investigate the thermal history of the sample. Equant, anhedral zircon grains that probably formed in the gabbronorite, referred to as type-1, have consistent U?Pb ages of 4332 7 Ma. A similar age of 4335 5 Ma was obtained from acicular zircon (type-2) grains interpreted to have formed from impact melt. A polycrystalline zircon aggregate (type-3) occurs as a rim around a baddeleyite grain and has a much younger age of 3929 10 Ma, similar to the 3936 17 Ma age of apatite grains found in the thin section. A combined apatite-type-3 zircon age of 3934 12 Ma is proposed as the age of the Serenitatis impact event and associated thermal pulse. X-ray mapping andelectron probe analyses showed that Ti is inhomogeneous in the zircon grains on the sub-micrometer scale. However, model temperatures estimated from SHRIMP analyses of Ti-concentration in the 10 lm diameter spots on the polished surfaces of type-1 and type-2 zircons range between about 1300 and 900 C respectively, whereas Ti-concentrations determined for the type-3 zircon are higher at about 1400?1500 C. A combination of U?Pb ages, Ti-concentration data and detailed imaging and petrographic studies of the zircon grains shows that the gabbronorite parent of the zircon clasts formed shortly before the 4335 5 Ma impact, which mixed the clasts and the felsic melt and projected the sample closer to the surface where fast cooling resulted in the crystallization of acicular zircon (type-2). The 3934 12 Ma Serenitatis event resulted in partial remelting of the glass and formation of polycrystalline zircon (type-3). This event also reset the U?Pb system of apatite, formed merrillite coronas around some apatite grains, and probably re-equilibrated some pyroxenes in the clasts. Although there have been arguments for pre-3.9 Ga impacts based on other types of samples, the age of the acicular zircon at 4335 5 Ma provides the first evidence of impact melt significantly predating the lunar cataclysm. Our data, combined with other chronological results, demonstrate the occurrence of pre-3.9 Ga impacts on the Moon and suggest that the lunar impact history consisted of a series of intense bombardment episodes interspersed with relatively calm periods of low impact flux

T Lymphocyte Potential Marks the Emergence of Definitive Hematopoietic Progenitors in Human Pluripotent Stem Cell Differentiation Cultures

SummaryThe efficient generation of hematopoietic stem cells from human pluripotent stem cells is dependent on the appropriate specification of the definitive hematopoietic program during differentiation. In this study, we used T lymphocyte potential to track the onset of definitive hematopoiesis from human embryonic and induced pluripotent stem cells differentiated with specific morphogens in serum- and stromal-free cultures. We show that this program develops from a progenitor population with characteristics of hemogenic endothelium, including the expression of CD34, VE-cadherin, GATA2, LMO2, and RUNX1. Along with T cells, these progenitors display the capacity to generate myeloid and erythroid cells. Manipulation of Activin/Nodal signaling during early stages of differentiation revealed that development of the definitive hematopoietic progenitor population is not dependent on this pathway, distinguishing it from primitive hematopoiesis. Collectively, these findings demonstrate that it is possible to generate T lymphoid progenitors from pluripotent stem cells and that this lineage develops from a population whose emergence marks the onset of human definitive hematopoiesis

A scoping review of nurse-led randomised controlled trials

Background: Nurses comprise the largest portion of the healthcare workforce worldwide. However, nurse representation in the leadership of clinical research and research funding is largely unknown. The Australasian Nursing and Midwifery Clinical Trials Network was established to provide a coordinated network, focussed on building research capacity in nursing and midwifery. To support this work, this scoping review of nurse-led randomised controlled trials was conducted to summarise research activity, as well as highlight future research directions, gaps and resources. Midwife-led trials will be reported elsewhere. Aim: To quantify number, type and quality of nurse-led randomised controlled trials registered between 2000–2021. Design: A scoping review of RCTs. Data Sources: Medline, Emcare and Scopus were searched from 2000 to August 2021. ANZCTR, NHMRC, MRFF and HRC (NZ) registries were searched from inception to July 2021. Review Methods: This review was informed by the JBI scoping review framework using the PRISMA-ScR. Results: Our search yielded 186 nurse-led publications and 279 registered randomised controlled trials. Multiple trials had the same nurse leaders. There were more registrations than publications. Publications were predominantly of high methodological quality; however, there was a reliance on active controls and blinding low. Trial registrations indicate that universities and hospital/healthcare organisations were the major sources of funding, while publications indicate that Governments and the National Health and Medical Research Council were the main funding bodies. Conclusion: A small number of high-quality, large-scale, nationally funded randomised controlled trials were identified, with a larger number of locally funded small trials. There was a disparity between the number of registered trials and those published. Additional infrastructure, funding and career frameworks are needed to enable nurses to design, conduct and publish clinical trials that inform the health system and improve health outcomes. Relevance to Clinical Practice: Research initiated and led by nurses has the potential to improve the health and well-being of individuals and communities, and current nurse-led research is of high methodological quality; however, there were very few nurse-led RCTs, conducted by a small pool of nurse researchers. This gap highlights the need for support in the design, conduct and publishing of nurse-led RCTs. Patient or Public Contribution: This is a scoping review; therefore, patient or public contribution is not applicable

Environmental stressors may cause unpredicted, notably lagged life-history responses in adults of the planktivorous Atlantic herring

Here we challenge traditional views on the direction of change in teleost body condition and reproductive traits in response to abiotic and biotic factors by studying the data-rich, planktivorous Norwegian spring-spawning herring (NSSH), a member of the abundant Atlantic herring (Clupea harengus) stock complex. To test potential influential factors, we focused on the last twenty years, i.e. a period with ocean warming, a transient but significant drop in zooplankton biomass, and accelerating interspecific competition resulting from primarily Atlantic mackerel (Scomber scombrus) entering these high-latitude waters in large quantities, “the new mackerel era” in the Nordic Seas. Adult NSSH concurrently allocated relatively less to growth in length than weight resulting in higher body condition. Growth likely decreased in warmer waters under stiff prey competition to support reproductive costs. Condition and reproductive responses were not only immediate but were also lagged by three seasons, corresponding to the period when new oocytes are produced. Furthermore, fecundity increased in warmer waters while egg size dropped. Hence, fine-tuned trade-off mechanisms were apparent and varied. We demonstrate that evaluations of reproductive trade-offs based on pooled data are misleading; poor- and good-condition NSSH followed different reproductive trajectories. These findings emphasize difficult-to-predict trends in life-history traits should be tracked longitudinally by the individuals and their aggregate cohort, as they are linked to complex overarching environmental phenomena, like ecosystem carrying capacity and climate fluctuations.publishedVersio

Midwife led randomised controlled trials in Australia and New Zealand: A scoping review

Background: Midwives are the largest workforce involved in caring for pregnant women and their babies, and are well placed to translate research into practice and ensure midwifery priorities are appropriately targeted in researched. Currently, the number and focus of randomised controlled trials led by midwives in Australia and New Zealand is unknown. The Australasian Nursing and Midwifery Clinical Trials Network was established in 2020 to build nursing and midwifery research capacity. To aid this, scoping reviews of the quality and quantity of nurse and midwife led trials were undertaken. Aim: To identify midwife led trials conducted between 2000 and 2021 in Australia and New Zealand. Methods: This review was informed by the JBI scoping review framework. Medline, Emcare, and Scopus were searched from 2000-August 2021. ANZCTR, NHMRC, MRFF, and HRC (NZ) registries were searched from inception to July 2021. Findings: Of 26,467 randomised controlled trials registered on the Australian and New Zealand Clinical Trials Registry, 50 midwife led trials, and 35 peer-reviewed publications were identified. Publications were of moderate to high quality with scores limited due to an inability to blind participants or clinicians. Blinding of assessors was included in 19 published trials. Discussion: Additional support for midwives to design and conduct trials and publish findings is required. Further support is needed to translate registration of trial protocols into peer reviewed publications. Conclusion: These findings will inform the Australasian Nursing and Midwifery Clinical Trials Network plans to promote quality midwife led trials

Recent Experimental Tests of Special Relativity

We review our recent Michelson-Morley (MM) and Kennedy-Thorndike (KT) experiment, which tests Lorentz invariance in the photon sector, and report first results of our ongoing atomic clock test of Lorentz invariance in the matter sector. The MM-KT experiment compares a cryogenic microwave resonator to a hydrogen maser, and has set the most stringent limit on a number of parameters in alternative theories to special relativity. We also report first results of a test of Lorentz invariance in the SME (Standard Model Extension) matter sector, using Zeeman transitions in a laser cooled Cs atomic fountain clock. We describe the experiment together with the theoretical model and analysis. Recent experimental results are presented and we give a first estimate of components of the $\tilde{c}^p$ parameters of the SME matter sector. A full analysis of systematic effects is still in progress, and will be the subject of a future publication together with our final results. If confirmed, the present limits would correspond to first ever measurements of some $\tilde{c}^p$ components, and improvements by 11 and 14 orders of magnitude on others.Comment: 29 pages. Contribution to Springer Lecture Notes, "Special Relativity - Will it survive the next 100 years ?", Proceedings, Potsdam, 200

First-light LBT nulling interferometric observations: warm exozodiacal dust resolved within a few AU of eta Corvi

We report on the first nulling interferometric observations with the Large Binocular Telescope Interferometer (LBTI), resolving the N' band (9.81 - 12.41 um) emission around the nearby main-sequence star eta Crv (F2V, 1-2 Gyr). The measured source null depth amounts to 4.40% +/- 0.35% over a field-of-view of 140 mas in radius (~2.6\,AU at the distance of eta Corvi) and shows no significant variation over 35{\deg} of sky rotation. This relatively low null is unexpected given the total disk to star flux ratio measured by Spitzer/IRS (~23% across the N' band), suggesting that a significant fraction of the dust lies within the central nulled response of the LBTI (79 mas or 1.4 AU). Modeling of the warm disk shows that it cannot resemble a scaled version of the Solar zodiacal cloud, unless it is almost perpendicular to the outer disk imaged by Herschel. It is more likely that the inner and outer disks are coplanar and the warm dust is located at a distance of 0.5-1.0 AU, significantly closer than previously predicted by models of the IRS spectrum (~3 AU). The predicted disk sizes can be reconciled if the warm disk is not centrosymmetric, or if the dust particles are dominated by very small grains. Both possibilities hint that a recent collision has produced much of the dust. Finally, we discuss the implications for the presence of dust at the distance where the insolation is the same as Earth's (2.3 AU).Comment: 9 pages, 6 figures, accepted for publication in Ap