Treatment in the Morning versus Evening (TIME) Study:Feasibility of an Online Study

Aims: The Treatment in Morning versus Evening (TIME) pilot study sought to establish the feasibility of an onlineonly study detecting whether evening dosing of antihypertensives is more cardio protective than morning dosing.Methods: The TIME study uses a prospective, randomised, open-label, blinded end-point (PROBE) design. In response to various forms of advertising, patients from primary and secondary care, and databases of patients who had previously consented to being contacted about research in the UK, enrolled on the study website (www.timestudy.co.uk). Furthermore, 1,794 hypertensive subjects were written to in three primary care practices as a form of targeted advertising. Participants had to be over 18, prescribed at least one hypertensive drug and have a valid email address. Subjects self-registered, consented, and entered demographics and drug treatments online, before being randomised to taking their antihypertensive therapy in the morning or evening. Automated email followup was used to track patient reported cardiovascular outcomes for the year-long pilot study.Result: 355 participants were randomised and followed up for ≥ 12 months. During this period, 14 participants withdrew from the randomised time of treatment. 59 patients were randomised from 3 practices which wrote to patients publicising the study, giving a rate of 33 randomised per 1,000 patients written to. The 10-year ASSIGN cardiovascular risk of the randomised participants varied by age; 21% for all ages (n=355), 25% for >55 yrs (n=269), 27% for >60 yrs (n=227) and 30% for >65 yrs (n=150). Based on participant cardiovascular risk during the pilot, a full trial with 80% power to detect a 20% improved outcome of nocturnal dosing would require 631 events to occur.Conclusion: The TIME study pilot achieved recruitment efficiently. Based on the pilot data, the TIME study appears viable and has been funded by the British Heart Foundation to recruit over 10,269 subjects and to follow them up for 4 years

A study of autonomy in decapod crustacea

Autotomy is the process whereby an animal can discard a part of it's body from a preformed breakage plane. This study examines the natural occurrence of limb autotomy in the crab Carcinus maenas in the Yealm estuary, Devon; and the nervous control of limb autotomy in the hermit crab Pagurus bernhardus and the shore crab Carcinus maenas. Of the crabs caught in the Yealm estuary in monthly samples between February 1976 and January 1977, 13.2% had lost one or more limbs, with males showing a greater incidence of autotomy (14.5%) than females (12.2%). There is a significant positive relationship between crab's size and incidence of autotomy and seasonal changes in the incidence of autotomy can be explained in terms of alterations of the mean size of crabs caught in each monthly sample. Limb autotomy in Pagurus and Carcinus results from limb injury and coactivation of the two BI levator muscles. The smaller posterior levator muscle (PL) rotates to direct isometric force from the large anterior levator muscle (AL) onto a plug in the breakage plane which encircles the BI and cause autotomy. During normal locomotion, although the PL muscle is electrically active it's tendon does not rotate and AL force is directed away from the plug in the breakage plane. The nervous control of limb autotomy is a combination of injury induced central command and feedback from a peripheral sense organ. Injury causes high frequency excitation of AL motor neurones and inhibition of PL motor neurones. The PL muscle rotates, as during autotomy, when the sense organ CSD1 is stimulated by strong isometric contractions of the AL muscle. This investigation shows that PL rotation at autotomy results from such stimulation of CSD1 and not central nervous command. Accidental autotomy in inappropriate circumstances is prevented when CSD 1 inhibits AL contraction, inhibition which is avoided by injury induced excitation of AL motor neurones to cause autotomy.<p

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Peer navigation for clients on addiction treatment waiting lists

Peer navigation has potential to overcome barriers and improve skills to enhance recovery. We piloted peer navigation with clients on Turning Point’s Eastern Treatment Services’ waiting list. Eligible clients (n=25) were referred to a peer worker, for recovery capital (REC-CAP) baseline assessment and goal setting, and again at 4- and 12-weeks. Of 25 participants (55% male), mean age was 44 and the primary drug of concern for most (n=18; 72%) was alcohol. Goals included attending recovery groups, engaging with services, and improving relationships. Qualitative findings indicate benefits of navigation, including readiness for treatment. This study builds on our program of research on how peer navigation can improve recovery skills and connection. Peer workers can play an important role in a waiting list setting, and results support investing in a larger trial

Addressing statistical biases in nucleotide-derived protein databases for proteogenomic search strategies

[Image: see text] Proteogenomics has the potential to advance genome annotation through high quality peptide identifications derived from mass spectrometry experiments, which demonstrate a given gene or isoform is expressed and translated at the protein level. This can advance our understanding of genome function, discovering novel genes and gene structure that have not yet been identified or validated. Because of the high-throughput shotgun nature of most proteomics experiments, it is essential to carefully control for false positives and prevent any potential misannotation. A number of statistical procedures to deal with this are in wide use in proteomics, calculating false discovery rate (FDR) and posterior error probability (PEP) values for groups and individual peptide spectrum matches (PSMs). These methods control for multiple testing and exploit decoy databases to estimate statistical significance. Here, we show that database choice has a major effect on these confidence estimates leading to significant differences in the number of PSMs reported. We note that standard target:decoy approaches using six-frame translations of nucleotide sequences, such as assembled transcriptome data, apparently underestimate the confidence assigned to the PSMs. The source of this error stems from the inflated and unusual nature of the six-frame database, where for every target sequence there exists five “incorrect” targets that are unlikely to code for protein. The attendant FDR and PEP estimates lead to fewer accepted PSMs at fixed thresholds, and we show that this effect is a product of the database and statistical modeling and not the search engine. A variety of approaches to limit database size and remove noncoding target sequences are examined and discussed in terms of the altered statistical estimates generated and PSMs reported. These results are of importance to groups carrying out proteogenomics, aiming to maximize the validation and discovery of gene structure in sequenced genomes, while still controlling for false positives

Fam151b, the mouse homologue of C.elegans menorin gene, is essential for retinal function

Fam151b is a mammalian homologue of the C. elegans menorin gene, which is involved in neuronal branching. The International Mouse Phenotyping Consortium (IMPC) aims to knock out every gene in the mouse and comprehensively phenotype the mutant animals. This project identified Fam151b homozygous knock-out mice as having retinal degeneration. We show they have no photoreceptor function from eye opening, as demonstrated by a lack of electroretinograph (ERG) response. Histological analysis shows that during development of the eye the correct number of cells are produced and that the layers of the retina differentiate normally. However, after eye opening at P14, Fam151b mutant eyes exhibit signs of retinal stress and rapidly lose photoreceptor cells. We have mutated the second mammalian menorin homologue, Fam151a, and homozygous mutant mice have no discernible phenotype. Sequence analysis indicates that the FAM151 proteins are members of the PLC-like phosphodiesterase superfamily. However, the substrates and function of the proteins remains unknown