Pharmacokinetics of once-daily extended-release tacrolimus tablets versus twice-daily capsules in de novo liver transplant

The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR-Tac = 75%; day 14: LCPT = 86%, IR-Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration-time curve for both LCPT and IR-Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P \u3c .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty-five patients completed the extended-use period. No significant differences in adverse events were seen between groups. Incidence of biopsy-proven acute rejection (LCPT = 6 and IR-Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed-release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation

Men, maternity and moral residue:negotiating the moral demands of the transition to first time fatherhood

This article discusses men's transition to first time fatherhood, with a focus on the way they recognise various in-tension moral demands and negotiate an appropriate role for themselves. The findings are taken from a longitudinal study, drawing on elements of grounded theory, comprising a series of face-to-face and telephone interviews with 11 men over a 9-month period from the 12(th) week of pregnancy to 8 weeks after the birth. The analysis focuses on men's feelings and experience of exclusion and participation, and their response and reaction to that experience. The findings present two descriptive themes, ‘on the inside looking in’ and ‘present but not participating’, followed by third theme ‘deference and support: a moral response’ that exposes the dilemmatic nature of men's experience and explains the participants’ apparent acceptance of being less involved. The discussion explores the concept of moral residue, arguing that while deference and support may be an appropriate role for fathers in the perinatal period it may also be a compromise that leads to feelings of uncertainty and frustration, which is a consequence of being in a genuinely dilemmatic situation

Reducing car-use for leisure: can organised walking groups switch from car travel to bus and train walks?

This paper deals with the significant leisure travel sector, focusing on the attitudes of organised walking groups towards public transport use. A series of interviews with walking group leaders explored the design of organised walks, and factors affecting journeys to and from start points. The themes presented suggest an overlying group culture involving mainly circular walks, reached by car. The research indicates an underlying engrained dependency on cars to reach walks and a degree of opposition to using public transport, which generally contradicts widely–held attitudes towards protecting the environment. Future research should focus more in depth on the long-term removal of psychological barriers to using public transport for leisure, and persuasive measures aimed at groups

Childhood leukemia: electric and magnetic fields as possible risk factors.

Numerous epidemiologic studies have reported associations between measures of power-line electric or magnetic fields (EMFs) and childhood leukemia. The basis for such associations remains unexplained. In children, acute lymphoblastic leukemia represents approximately three-quarters of all U.S. leukemia types. Some risk factors for childhood leukemia have been established, and others are suspected. Pathogenesis, as investigated in animal models, is consistent with the multistep model of acute leukemia development. Studies of carcinogenicity in animals, however, are overwhelmingly negative and do not support the hypothesis that EMF exposure is a significant risk factor for hematopoietic neoplasia. We may fail to observe effects from EMFs because, from a mechanistic perspective, the effects of EMFs on biology are very weak. Cells and organs function despite many sources of chemical "noise" (e.g., stochastic, temperature, concentration, mechanical, and electrical noise), which exceed the induced EMF "signal" by a large factor. However, the inability to detect EMF effects in bioassay systems may be caused by the choice made for "EMF exposure." "Contact currents" or "contact voltages" have been proposed as a novel exposure metric, because their magnitude is related to measured power-line magnetic fields. A contact current occurs when a person touches two conductive surfaces at different voltages. Modeled analyses support contact currents as a plausible metric because of correlations with residential magnetic fields and opportunity for exposure. The possible role of contact currents as an explanatory variable in the reported associations between EMFs and childhood leukemia will need to be clarified by further measurements, biophysical analyses, bioassay studies, and epidemiology

The Transitional Stripped-Envelope SN 2008ax: Spectral Evolution and Evidence for Large Asphericity

Supernova (SN) 2008ax in NGC 4490 was discovered within hours after shock breakout, presenting the rare opportunity to study a core-collapse SN beginning with the initial envelope-cooling phase immediately following shock breakout. We present an extensive sequence of optical and near-infrared spectra, as well as three epochs of optical spectropolarimetry. Our initial spectra, taken two days after shock breakout, are dominated by hydrogen Balmer lines at high velocity. However, by maximum light, He I lines dominated the optical and near-infrared spectra, which closely resembled those of normal Type Ib supernovae (SNe Ib) such as SN 1999ex. This spectroscopic transition defines Type IIb supernovae, but the strong similarity of SN 2008ax to normal SNe Ib beginning near maximum light, including an absorption feature near 6270A due to H-alpha at high velocities, suggests that many objects classified as SNe Ib in the literature may have ejected similar amounts of hydrogen as SN 2008ax, roughly a few x 0.01 M_sun. Early-time spectropolarimetry (6 and 9 days after shock breakout) revealed strong line polarization modulations of 3.4% across H-alpha, indicating the presence of large asphericities in the outer ejecta. The continuum shares a common polarization angle with the hydrogen, helium, and oxygen lines, while the calcium and iron absorptions are oriented at different angles. This is clear evidence of deviations from axisymmetry even in the outer ejecta. Intrinsic continuum polarization of 0.64% only nine days after shock breakout shows that the outer layers of the ejecta were quite aspherical. A single epoch of late-time spectropolarimetry, as well as the shapes of the nebular line profiles, demonstrate that asphericities extended from the outermost layers all the way down to the center of this SN. [Abridged]Comment: 24 pages, 21 figures, 4 tables, appendix, minor revisions to match version accepted by Ap

Habilitation provision for children and young people with vision impairment in the United Kingdom: A lack of clarity leading to inconsistencies

The key to empowering and supporting children and young people (CYP) with vision impairment (VI) to achieve their potential lies in the delivery of habilitation training. Evidence has revealed that provision of habilitation services across the United Kingdom was inconsistent, with CYP with VI not receiving services in some areas. This research explored the accessibility and quality of habilitation provision for CYP with VI via two studies: (1) 12 qualitative case studies of habilitation practice and (2) surveys of habilitation training experiences, with CYP with VI (n = 43) and with parents of CYP with VI (n = 68). Five themes were identified highlighting inconsistencies and variability in the delivery of habilitation training in recent years, a lack of focus on independent living skills training, on social inclusion and emotional well-being, a lack of support for parents and a lack of clarity with regard to the definition of habilitation, and who is responsible for providing training

Key issues in recruitment to randomised controlled trials with very different interventions: a qualitative investigation of recruitment to the SPARE trial (CRUK/07/011)

<p>Abstract</p> <p>Background</p> <p>Recruitment to randomised controlled trials (RCTs) with very different treatment arms is often difficult. The ProtecT (Prostate testing for cancer and Treatment) study successfully used qualitative research methods to improve recruitment and these methods were replicated in five other RCTs facing recruitment difficulties. A similar qualitative recruitment investigation was undertaken in the SPARE (Selective bladder Preservation Against Radical Excision) feasibility study to explore reasons for low recruitment and attempt to improve recruitment rates by implementing changes suggested by qualitative findings.</p> <p>Methods</p> <p>In Phase I of the investigation, reasons for low levels of recruitment were explored through content analysis of RCT documents, thematic analysis of interviews with trial staff and recruiters, and conversation analysis of audio-recordings of recruitment appointments. Findings were presented to the trial management group and a plan of action was agreed. In Phase II, changes to design and conduct were implemented, with training and feedback provided for recruitment staff.</p> <p>Results</p> <p>Five key challenges to trial recruitment were identified in Phase I: (a) Investigators and recruiters had considerable difficulty articulating the trial design in simple terms; (b) The recruitment pathway was complicated, involving staff across different specialties/centres and communication often broke down; (c) Recruiters inadvertently used 'loaded' terminology such as 'gold standard' in study information, leading to unbalanced presentation; (d) Fewer eligible patients were identified than had been anticipated; (e) Strong treatment preferences were expressed by potential participants and trial staff in some centres. In Phase II, study information (patient information sheet and flowchart) was simplified, the recruitment pathway was focused around lead recruiters, and training sessions and 'tips' were provided for recruiters. Issues of patient eligibility were insurmountable, however, and the independent Trial Steering Committee advised closure of the SPARE trial in February 2010.</p> <p>Conclusions</p> <p>The qualitative investigation identified the key aspects of trial design and conduct that were hindering recruitment, and a plan of action that was acceptable to trial investigators and recruiters was implemented. Qualitative investigations can thus be used to elucidate challenges to recruitment in trials with very different treatment arms, but require sufficient time to be undertaken successfully.</p> <p>Trial Registration</p> <p>CRUK/07/011; <a href="http://www.controlled-trials.com/ISRCTN61126465">ISRCTN61126465</a></p

LoCuSS: Luminous infrared galaxies in the merging cluster Abell 1758 at z=0.28

We present the first galaxy evolution results from the Local Cluster Substructure Survey (LoCuSS), a multi-wavelength survey of 100 X-ray selected galaxy clusters at 0.15<z<0.30. LoCuSS combines far-UV through far-IR observations of cluster galaxies with gravitational lensing analysis and X-ray data to investigate the interplay between the hierarchical assembly of clusters and the evolution of cluster galaxies. Here we present new panoramic Spitzer/MIPS 24micron observations of the merging cluster Abell 1758 at z=0.279 spanning 6.5x6.5Mpc and reaching a 90% completeness limit of 400uJy. We estimate a global cluster SFR of 910\pm320 M_sun/yr within 3 Mpc of the cluster centre, originating from 42 galaxies with L_IR > 5x10^10 L_sun. The obscured activity in A1758 is therefore comparable with that in Cl 0024+1654, the most active cluster previously studied at 24um. The obscured galaxies faithfully trace the cluster potential as revealed by the weak-lensing mass map of the cluster, including numerous mass peaks at R~2-3Mpc that are likely associated with infalling galaxy groups and filamentary structures. However the core (R<500kpc) of A1758N is 2x more active in the IR than that of A1758S, likely reflecting differences in the recent dynamical history of the two clusters. The 24micron results from A1758 therefore suggest that dust-obscured cluster galaxies are common in merging clusters and suggests that obscured activity in clusters is triggered by both the details of cluster-cluster mergers and processes that operate at larger radii including those within in-falling groups. Our ongoing far-UV through far-IR observations of a large sample of clusters should allow us to disentangle the different physical processes responsible for triggering obscured star formation in clusters.Comment: 13 pages, 9 figures. Accepted for publication in MNRA