Why are feasibility studies accessing routinely collected health data? A systematic review

BACKGROUND: Feasibility trials are often undertaken to determine whether a larger randomised controlled trial (RCT) is achievable. In a recent review, 15 feasibility trials accessed routinely collected health data (RCHD) from UK national databases and registries. This paper looks at attributes of these trials and the reasons why they accessed RCHD. METHODS: We extracted data from all publicly available sources for the 15 feasibility studies found in a previous review of trials successfully accessing RCHD in the UK between 2013–2018 for the purpose of informing or supplementing participant data. We extracted trial characteristics, the registry accessed, and the way the RCHD was used. RESULTS: The 15 feasibility RCTs were conducted in a variety of disease areas, and were generally small (median sample size 100, range 41–4061) and individually randomised (60%, 9/15). The primary trial outcome was predominantly administrative (non-clinical) (80%, 12/15) such as feasibility of patient recruitment. They were more likely to recruit from secondary care (67%, 10/15) settings than primary (33%, 5/15). NHS Digital was the most commonly accessed registry (33% (5/15)) with SAIL databank (20% (3/15)), electronic Data Research and Innovation Service (eDRIS) and Paediatric Intensive Care Audit Network (PICANET) (each 13% 2/15) also being accessed. Where the information was clear, the trials used RCHD for data collection during the trial (47%, 7/15), follow-up after the trial (27%, 4/15) and recruitment (13%, 2/15). CONCLUSIONS: Between 2013 and 2018, 15 feasibility trials successfully accessed UK RCHD. Feasibility trials would benefit, as with other trials, from guidance on reporting the use of RCHD in protocols and publications

Axion Protection from Flavor

The QCD axion fails to solve the strong CP problem unless all explicit PQ violating, Planck-suppressed, dimension n<10 operators are forbidden or have exponentially small coefficients. We show that all theories with a QCD axion contain an irreducible source of explicit PQ violation which is proportional to the determinant of the Yukawa interaction matrix of colored fermions. Generically, this contribution is of low operator dimension and will drastically destabilize the axion potential, so its suppression is a necessary condition for solving the strong CP problem. We propose a mechanism whereby the PQ symmetry is kept exact up to n=12 with the help of the very same flavor symmetries which generate the hierarchical quark masses and mixings of the SM. This "axion flavor protection" is straightforwardly realized in theories which employ radiative fermion mass generation and grand unification. A universal feature of this construction is that the heavy quark Yukawa couplings are generated at the PQ breaking scale.Comment: 16 pages, 2 figure

Delineation of Culicoides species by morphology and barcode exemplified by three new species of the subgenus Culicoides (Diptera: Ceratopogonidae) from Scandinavia

BACKGROUND: Culicoides biting midges (Diptera: Ceratopogonidae) cause biting nuisance to livestock and humans and are vectors of a range of pathogens of medical and veterinary importance. Despite their economic significance, the delineation and identification of species where only morphology is considered, as well as the evolutionary relationships between species within this genus remains problematic. In recent years molecular barcoding has assisted substantially in the identification of biting midges in the multiple entomological survey projects which were initiated in many European countries following the bluetongue outbreak in 2006–2009. These studies revealed potentially new species and “species-complexes” with large genetic and morphological variability. Here we use molecular barcoding, together with morphological analysis, to study subgenus Culicoides Latreille from Scandinavia with focus on three potentially new species. METHODS: Biting midges were collected at various sites in Denmark and Sweden. Culicoides specimens were described by variation of a fragment of their cytochrome c oxidase subunit 1 (COI) gene sequence and wing, palp and antennal characters. RESULTS: It is shown that three new species initially separated by DNA barcoding with mitochondrial COI can be distinguished by morphological characters. In this context a key to Scandinavian subgenus Culicoides using wing and maxillary palp characters is presented. The key is including the three new species Culicoides boyi, Culicoides selandicus and Culicoides kalix. CONCLUSION: Three new species of Culicoides biting midges were identified and could be identified by both molecular and morphological differences. Evaluation of differences between and within taxa of biting midges using COI barcode yielded a rough estimate of species delineation; interspecies differences across Culicoides subgenera approaches 20%, whereas intraspecies differences are below 4% and in most cases below 1%. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13071-015-0750-4) contains supplementary material, which is available to authorized users

Quantifying the potential for bluetongue virus transmission in Danish cattle farms

We used a mechanistic transmission model to estimate the number of infectious bites (IBs) generated per bluetongue virus (BTV) infected host (cattle) using estimated hourly microclimatic temperatures at 22,004 Danish cattle farms for the period 2000–2016, and Culicoides midge abundance based on 1,453 light-trap collections during 2007–2016. We used a range of published estimates of the duration of the hosts’ infectious period and equations for the relationship between temperature and four key transmission parameters: extrinsic incubation period, daily vector survival rate, daily vector biting rate and host-to-vector transmission rate resulting in 147,456 combinations of daily IBs. More than 82% combinations of the parameter values predicted > 1 IBs per host. The mean IBs (10–90th percentiles) for BTV per infectious host were 59 (0–73) during the transmission period. We estimated a maximum of 14,954 IBs per infectious host at some farms, while a best-case scenario suggested transmission was never possible at some farms. The use of different equations for the vector survival rate and host-to-vector transmission rates resulted in large uncertainty in the predictions. If BTV is introduced in Denmark, local transmission is very likely to occur. Vectors infected as late as mid-September (early autumn) can successfully transmit BTV to a new host until mid-November (late autumn)

Protocol for the saMS trial (supportive adjustment for multiple sclerosis): a randomized controlled trial comparing cognitive behavioral therapy to supportive listening for adjustment to multiple sclerosis

BackgroundMultiple Sclerosis (MS) is an incurable, chronic, potentially progressive and unpredictable disease of the central nervous system. The disease produces a range of unpleasant and debilitating symptoms, which can have a profound impact including disrupting activities of daily living, employment, income, relationships, social and leisure activities, and life goals. Adjusting to the illness is therefore particularly challenging. This trial tests the effectiveness of a cognitive behavioural intervention compared to supportive listening to assist adjustment in the early stages of MS.MethodsThis is a two arm randomized multi-centre parallel group controlled trial. 122 consenting participants who meet eligibility criteria will be randomly allocated to receive either Cognitive Behavioral Therapy or Supportive Listening. Eight one hour sessions of therapy (delivered over a period of 10 weeks) will be delivered by general nurses trained in both treatments. Self-report questionnaire data will be collected at baseline (0 weeks), mid-therapy (week 5 of therapy), post-therapy (15 weeks) and at six months (26 weeks) and twelve months (52 weeks) follow-up. Primary outcomes are distress and MS-related social and role impairment at twelve month follow-up. Analysis will also consider predictors and mechanisms of change during therapy. In-depth interviews to examine participants’ experiences of the interventions will be conducted with a purposively sampled sub-set of the trial participants. An economic analysis will also take place. DiscussionThis trial is distinctive in its aims in that it aids adjustment to MS in a broad sense. It is not a treatment specifically for depression. Use of nurses as therapists makes the interventions potentially viable in terms of being rolled out in the NHS. The trial benefits from incorporating patient input in the development and evaluation stages. The trial will provide important information about the efficacy, cost-effectiveness and acceptability of the interventions as well as mechanisms of psychosocial adjustment.Trial registrationCurrent Controlled Trials ISRCTN91377356<br/

The Effects of Previous Error and Success in Alzheimer’s Disease and Mild Cognitive Impairment

This work investigated in Alzheimer’s disease dementia (AD), whether the probability of making an error on a task (or a correct response) was influenced by the outcome of the previous trials. We used the antisaccade task (AST) as a model task given the emerging consensus that it provides a promising sensitive and early biological test of cognitive impairment in AD. It can be employed equally well in healthy young and old adults, and in clinical populations. This study examined eye-movements in a sample of 202 participants (42 with dementia due to AD; 65 with mild cognitive impairment (MCI); 95 control participants). The findings revealed an overall increase in the frequency of AST errors in AD and MCI compared to the control group, as predicted. The errors on the current trial increased in proportion to the number of consecutive errors on the previous trials. Interestingly, the probability of errors was reduced on the trials that followed a previously corrected error, compared to the trials where the error remained uncorrected, revealing a level of adaptive control in participants with MCI or AD dementia. There was an earlier peak in the AST distribution of the saccadic reaction times for the inhibitory errors in comparison to the correct saccades. These findings revealed that the inhibitory errors of the past have a negative effect on the future performance of healthy adults as well as people with a neurodegenerative cognitive impairment

A Neptune-sized transiting planet closely orbiting a 5–10-million-year-old star

Theories of the formation and early evolution of planetary systems postulate that planets are born in circumstellar disks, and undergo radial migration during and after dissipation of the dust and gas disk from which they formed^1, 2. The precise ages of meteorites indicate that planetesimals—the building blocks of planets—are produced within the first million years of a star’s life^3. Fully formed planets are frequently detected on short orbital periods around mature stars. Some theories suggest that the in situ formation of planets close to their host stars is unlikely and that the existence of such planets is therefore evidence of large-scale migration^4, 5. Other theories posit that planet assembly at small orbital separations may be common^6, 7, 8. Here we report a newly born, transiting planet orbiting its star with a period of 5.4 days. The planet is 50 per cent larger than Neptune, and its mass is less than 3.6 times that of Jupiter (at 99.7 per cent confidence), with a true mass likely to be similar to that of Neptune. The star is 5–10 million years old and has a tenuous dust disk extending outward from about twice the Earth–Sun separation, in addition to the fully formed planet located at less than one-twentieth of the Earth–Sun separation

Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

Beetle (Coleoptera: Scirtidae) Facilitation of Larval Mosquito Growth in Tree Hole Habitats is Linked to Multitrophic Microbial Interactions

Container-breeding mosquitoes, such as Aedes triseriatus, ingest biofilms and filter water column microorganisms directly to obtain the bulk of their nutrition. Scirtid beetles often co-occur with A. triseriatus and may facilitate the production of mosquito adults under low-resource conditions. Using molecular genetic techniques and quantitative assays, we observed changes in the dynamics and composition of bacterial and fungal communities present on leaf detritus and in the water column when scirtid beetles co-occur with A. triseriatus. Data from terminal restriction fragment polymorphism analysis indicated scirtid presence alters the structure of fungal communities in the water column but not leaf-associated fungal communities. Similar changes in leaf and water bacterial communities occurred in response to mosquito presence. In addition, we observed increased processing of leaf detritus, higher leaf-associated enzyme activity, higher bacterial productivity, and higher leaf-associated fungal biomass when scirtid beetles were present. Such shifts suggest beetle feeding facilitates mosquito production indirectly through the microbial community rather than directly through an increase in available fine particulate organic matter

A controlled trial of protein enrichment of meal replacements for weight reduction with retention of lean body mass

<p>Abstract</p> <p>Background</p> <p>While high protein diets have been shown to improve satiety and retention of lean body mass (LBM), this study was designed to determine effects of a protein-enriched meal replacement (MR) on weight loss and LBM retention by comparison to an isocaloric carbohydrate-enriched MR within customized diet plans utilizing MR to achieve high protein or standard protein intakes.</p> <p>Methods</p> <p>Single blind, placebo-controlled, randomized outpatient weight loss trial in 100 obese men and women comparing two isocaloric meal plans utilizing a standard MR to which was added supplementary protein or carbohydrate powder. MR was used twice daily (one meal, one snack). One additional meal was included in the meal plan designed to achieve individualized protein intakes of either 1) 2.2 g protein/kg of LBM per day [high protein diet (HP)] or 2) 1.1 g protein/kg LBM/day standard protein diet (SP). LBM was determined using bioelectrical impedance analysis (BIA). Body weight, body composition, and lipid profiles were measured at baseline and 12 weeks.</p> <p>Results</p> <p>Eighty-five subjects completed the study. Both HP and SP MR were well tolerated, with no adverse effects. There were no differences in weight loss at 12 weeks (-4.19 ± 0.5 kg for HP group and -3.72 ± 0.7 kg for SP group, p > 0.1). Subjects in the HP group lost significantly more fat weight than the SP group (HP = -1.65 ± 0.63 kg; SP = -0.64 ± 0.79 kg, P = 0.05) as estimated by BIA. There were no significant differences in lipids nor fasting blood glucose between groups, but within the HP group a significant decrease in cholesterol and LDL cholesterol was noted at 12 weeks. This was not seen in the SP group.</p> <p>Conclusion</p> <p>Higher protein MR within a higher protein diet resulted in similar overall weight loss as the standard protein MR plan over 12 weeks. However, there was significantly more fat loss in the HP group but no significant difference in lean body mass. In this trial, subject compliance with both the standard and protein-enriched MR strategy for weight loss may have obscured any effect of increased protein on weight loss demonstrated in prior weight loss studies using whole food diets.</p