The Ca2+ transient as a feedback sensor controlling cardiomyocyte ionic conductances in mouse populations.

Conductances of ion channels and transporters controlling cardiac excitation may vary in a population of subjects with different cardiac gene expression patterns. However, the amount of variability and its origin are not quantitatively known. We propose a new conceptual approach to predict this variability that consists of finding combinations of conductances generating a normal intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject variability. The method predicts that conductances of inward Ca2+ and outward K+ currents compensate each other to generate a normal Ca2+ transient in good quantitative agreement with current measurements in ventricular myocytes from hearts of different isogenic strains. Our results suggest that a feedback mechanism sensing the aggregate Ca2+ transient of the heart suffices to regulate ionic conductances

Patient experience of gastrointestinal endoscopy: Informing the development of the Newcastle ENDOPREM

Background Measuring patient experience is important for evaluating the quality of patient care, identifying aspects requiring improvement and optimising patient outcomes. Patient Reported Experience Measures (PREMs) should, ideally, be patient derived, however no such PREMs for gastrointestinal (GI) endoscopy exist. This study explored the experiences of patients undergoing GI endoscopy and CT colonography (CTC) in order to: identify aspects of care important to them; determine whether the same themes are relevant across investigative modalities; develop the framework for a GI endoscopy PREM. Methods Patients aged ≥18 years who had undergone oesophagogastroduodenoscopy (OGD), colonoscopy or CTC for symptoms or surveillance (but not within the national bowel cancer screening programme) in one hospital were invited to participate in semi-structured interviews. Recruitment continued until data saturation. Inductive thematic analysis was undertaken. Results 35 patients were interviewed (15 OGD, 10 colonoscopy, 10 CTC). Most patients described their experience chronologically, and five ‘procedural stages’ were evident: before attending for the test; preparing for the test; at the hospital, before the test; during the test; after the test. Six themes were identified: anxiety; expectations; choice & control; communication & information; comfort; embarrassment & dignity. These were present for all three procedures but not all procedure stages. Some themes were inter-related (eg, expectations & anxiety; communication & anxiety). Conclusion We identified six key themes encapsulating patient experience of GI procedures and these themes were evident for all procedures and across multiple procedure stages. These findings will be used to inform the development of the Newcastle ENDOPREM™

Structural analysis of herpes simplex virus by optical super-resolution imaging.

Herpes simplex virus type-1 (HSV-1) is one of the most widespread pathogens among humans. Although the structure of HSV-1 has been extensively investigated, the precise organization of tegument and envelope proteins remains elusive. Here we use super-resolution imaging by direct stochastic optical reconstruction microscopy (dSTORM) in combination with a model-based analysis of single-molecule localization data, to determine the position of protein layers within virus particles. We resolve different protein layers within individual HSV-1 particles using multi-colour dSTORM imaging and discriminate envelope-anchored glycoproteins from tegument proteins, both in purified virions and in virions present in infected cells. Precise characterization of HSV-1 structure was achieved by particle averaging of purified viruses and model-based analysis of the radial distribution of the tegument proteins VP16, VP1/2 and pUL37, and envelope protein gD. From this data, we propose a model of the protein organization inside the tegument.This work was supported by grants from the Leverhulme Trust (grant RPG-2012-793), the Royal Society (University Research Fellowship to C.M.C.), the Engineering and Physical Sciences Research Council, UK (grant EP/H018301/1) and by the Medical Research Council (grant MR/K015850/1).This is the final published version. It first appeared at http://www.nature.com/ncomms/2015/150122/ncomms6980/full/ncomms6980.html

Use of Two Self-referral Reminders and a Theory-Based Leaflet to Increase the Uptake of Flexible Sigmoidoscopy in the English Bowel Scope Screening Program: Results From a Randomized Controlled Trial in London

Background We previously initiated a randomized controlled trial to test the effectiveness of two self-referral reminders and a theory-based leaflet (sent 12 and 24 months after the initial invitation) to increase participation within the English Bowel Scope Screening program. Purpose This study reports the results following the second reminder. Methods Men and women included in the initial sample (n = 1,383) were re-assessed for eligibility 24 months after their invitation (12 months after the first reminder) and excluded if they had attended screening, moved away, or died. Eligible adults received the same treatment they were allocated 12 months previous, that is, no reminder (“control”), or a self-referral reminder with either the standard information booklet (“Reminder and Standard Information Booklet”) or theory-based leaflet designed using the Behavior Change Wheel (“Reminder and Theory-Based Leaflet”). The primary outcome was the proportion screened within each group 12 weeks after the second reminder. Results In total, 1,218 (88.1%) individuals were eligible. Additional uptake following the second reminder was 0.4% (2/460), 4.8% (19/399), and 7.9% (29/366) in the control, Reminder and Standard Information Booklet, and Reminder and Theory-Based Leaflet groups, respectively. When combined with the first reminder, the overall uptake for each group was 0.7% (3/461), 14.5% (67/461), and 21.5% (99/461). Overall uptake was significantly higher in the Reminder and Standard Information Booklet and Reminder and Theory-Based Leaflet groups than in the control (odds ratio [OR] = 26.1, 95% confidence interval [CI] = 8.1–84.0, p < .001 and OR = 46.9, 95% CI = 14.7–149.9, p < .001, respectively), and significantly higher in the Reminder and Theory-Based Leaflet group than in the Reminder and Standard Information Booklet group (OR = 1.8, 95% CI = 1.3–2.6, p < .001). Conclusion A second reminder increased uptake among former nonparticipants. The added value of the theory-based leaflet highlights a potential benefit to reviewing the current information booklet. Trials Registry Number ISRCTN44293755

Evolution of bias in different cosmological models

We study the evolution of the halo-halo correlation function and bias in four cosmological models (LCDM, OCDM, tauCDM, and SCDM) using very high-resolution N-body simulations. The high force and mass resolution allows dark matter (DM) halos to survive in the tidal fields of high-density regions and thus prevents the ambiguities related with the ``overmerging problem.'' This allows us to estimate for the first time the evolution of the correlation function and bias at small (down to ~100/h kpc) scales. We find that at all epochs the 2-point correlation function of galaxy-size halos xi_hh is well approximated by a power-law with slope ~1.6-1.8. The difference between the shape of xi_hh and the shape of the correlation function of matter results in the scale-dependent bias at scales <7/h Mpc, which we find to be a generic prediction of the hierarchical models. The bias evolves rapidly from a high value of ~2-5 at z~3-7 to the anti-bias of b~0.5-1 at small <5/h Mpc scales at z=0. We find that our results agree well with existing clustering data at different redshifts. Particularly, we find an excellent agreement in both slope and the amplitude between xi_hh(z=0) in our LCDM simulation and the galaxy correlation function measured using the APM galaxy survey. At high redshifts, the observed clustering of the Lyman-break galaxies is also well reproduced by the models. The agreement with the data at high and low z indicates the general success of the hierarchical models of structure formation in which galaxies form inside the host DM halos. (Abridged)Comment: submitted to the Astrophys.Journal; 21 pages, LaTeX (uses emulateapj.sty); full resolution versions of figs.1 and 2 are available at http://astro.nmsu.edu/~akravtso/GROUP/group_publications.html or at ftp://charon.nmsu.edu/pub/kravtsov/PAPERS/Bias

Uptake of Bowel Scope (Flexible Sigmoidoscopy) Screening in the English National Programme: the first 14 months

Objective To examine uptake in the first six pilot centres of the English Bowel Scope Screening (BSS) programme, which began in early 2013 and invites adults aged 55 for a one off Flexible Sigmoidoscopy. Methods Between March 2013 and May 2014 the six pilot centres sent 21,187 invitations. Using multivariate logistic regression analysis, we examined variation in uptake by gender, socioeconomic deprivation (using the Index of Multiple Deprivation), area-based ethnic diversity (proportion of non-white residents), screening centre, and appointment time (routine: daytime vs out-of-hours: evening/weekend). Results Uptake was 43.1%. Men were more likely to attend than women (45% vs 42%; OR 1.136, 95% CI 1.076, 1.199, p

Colorectal polyp outcomes after participation in the seAFOod polyp prevention trial: Evidence of rebound elevated colorectal polyp risk after short-term aspirin use

BACKGROUND: The seAFOod polyp prevention trial was a randomised, placebo-controlled, 2 × 2 factorial trial of aspirin 300 mg and eicosapentaenoic acid (EPA) 2000 mg daily in individuals who had a screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Aspirin treatment was associated with a 20% reduction in colorectal polyp number at BCSP surveillance colonoscopy 12 months later. It is unclear what happens to colorectal polyp risk after short-term aspirin use. AIM: To investigate colorectal polyp risk according to the original trial treatment allocation, up to 6 years after trial participation. METHODS: All seAFOod trial participants were scheduled for further BCSP surveillance and provided informed consent for the collection of colonoscopy outcomes. We linked BCSP colonoscopy data to trial outcomes data. RESULTS: In total, 507 individuals underwent one or more colonoscopies after trial participation. Individuals grouped by treatment allocation were well matched for clinical characteristics, follow-up duration and number of surveillance colonoscopies. The polyp detection rate (PDR; the number of individuals who had ≥1 colorectal polyp detected) after randomization to placebo aspirin was 71.1%. The PDR was 80.1% for individuals who had received aspirin (odds ratio [OR] 1.13 [95% confidence interval 1.02, 1.24]; p = 0.02). There was no difference in colorectal polyp outcomes between individuals who had been allocated to EPA compared with its placebo (OR for PDR 1.00 [0.91, 1.10]; p = 0.92). CONCLUSION: Individuals who received aspirin in the seAFOod trial demonstrated increased colorectal polyp risk during post-trial surveillance. Rebound elevated neoplastic risk after short-term aspirin use has important implications for aspirin cessation driven by age-related bleeding risk. ISRCTN05926847

Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies.

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin-proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.Infinitus China Ltd