Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence

Background: A lack of age-appropriate formulations can make it difficult to administer medicines to children. A manipulation of the dosage form may be required to achieve the required dose. This study aimed to describe medicines that are manipulated to achieve the required dose in paediatric practice.Method: A structured, undisguised observational study and postal survey. The observational study investigated drug manipulations occurring in clinical practice across three sites. The questionnaire, administered to a sample of paediatric nurses throughout the UK, surveyed manipulations conducted and nurses' experiences and views.Results: The observational study identified 310 manipulations, of which 62% involved tablets, 21% were intravenous drugs and 10% were sachets. Of the 54 observed manipulations 40 involved tablets with 65% of the tablets being cut and 30% dispersed to obtain a smaller dose. 188 manipulations were reported by questionnaire respondents, of these 46% involved tablets, 12% were intravenous drugs, and 12% were nebuliser solutions. Manipulations were predominantly, but not exclusively, identified in specialist clinical areas with more highly dependent patients. Questionnaire respondents were concerned about the accuracy of the dose achieved following manipulations and the lack of practice guidance.Conclusion: Manipulations to achieve the required dose occur throughout paediatric in-patient settings. The impact of manipulations on the efficacy of the drugs, the accuracy of the dose and any adverse effects on patients is not known. There is a need to develop evidence-based guidance for manipulations of medicines in children

Obligate Heterodimerization of the Archaeal Alba2 Protein with Alba1 Provides a Mechanism for Control of DNA Packaging

SummaryOrganisms growing at elevated temperatures face a particular challenge to maintain the integrity of their genetic material. All thermophilic and hyperthermophilic archaea encode one or more copies of the Alba (Sac10b) gene. Alba is an abundant, dimeric, highly basic protein that binds cooperatively and at high density to DNA. Sulfolobus solfataricus encodes a second copy of the Alba gene, and the Alba2 protein is expressed at ∼5% of the level of Alba1. We demonstrate by NMR, ITC, and crystallography that Alba2 exists exclusively as a heterodimer with Alba1 at physiological concentrations and that heterodimerization exerts a clear effect upon the DNA packaging, as observed by EM, potentially by changing the interface between adjacent Alba dimers in DNA complexes. A functional role for Alba2 in modulation of higher order chromatin structure and DNA condensation is suggested

Design, assessment, and in vivo evaluation of a computational model illustrating the role of CAV1 in CD4+ T-lymphocytes

Caveolin-1 (CAV1) is a vital scaffold protein heterogeneously expressed in both healthy and malignant tissue. We focus on the role of CAV1 when overexpressed in T-cell leukemia. Previously, we have shown that CAV1 is involved in cell-to-cell communication, cellular proliferation, and immune synapse formation; however, the molecular mechanisms have not been elucidated. We hypothesize that the role of CAV1 in immune synapse formation contributes to immune regulation during leukemic progression, thereby warranting studies of the role of CAV1 in CD4+ T-cells in relation to antigen-presenting cells. To address this need, we developed a computational model of a CD4+ immune effector T-cell to mimic cellular dynamics and molecular signaling under healthy and immunocompromised conditions (i.e., leukemic conditions). Using the Cell Collective computational modeling software, the CD4+ T-cell model was constructed and simulated under CAV1+/+, CAV1+/−, and CAV1−/− conditions to produce a hypothetical immune response. This model allowed us to predict and examine the heterogeneous effects and mechanisms of CAV1 in silico. Experimental results indicate a signature of molecules involved in cellular proliferation, cell survival, and cytoskeletal rearrangement that were highly affected by CAV1 knock out. With this comprehensive model of a CD4+ T-cell, we then validated in vivo protein expression levels. Based on this study, we modeled a CD4+ T-cell, manipulated gene expression in immunocompromised versus competent settings, validated these manipulations in an in vivo murine model, and corroborated acute T-cell leukemia gene expression profiles in human beings. Moreover, we can model an immunocompetent versus an immunocompromised microenvironment to better understand how signaling is regulated in patients with leukemia

Acute medical unit comprehensive geriatric assessment intervention study (AMIGOS)

<p>Abstract</p> <p>Background</p> <p>Many older people presenting to Acute Medical Units (AMU) are discharged after only a short stay (< 72 hours), yet many re-present to hospital or die within 1 year. Comprehensive Geriatric Assessment may improve patient outcomes for this group.</p> <p>Method</p> <p>Participants</p> <p>Patients aged > 70 years and scoring positive on a risk screening tool ('Identification of Seniors At Risk') who are discharged within 72 hours of attending an AMU with a medical crisis, recruited prior to discharge. Sample size is 400. Carers of participants will also be recruited.</p> <p>Intervention</p> <p>Assessment on the AMU and further out-patient management by a specialist physician in geriatric medicine. Assessment and further management will follow the principles of Comprehensive Geriatric Assessment, providing advice and support to primary care services.</p> <p>Design</p> <p>Multi-centre, individual patient randomised controlled trial comparing intervention with usual care.</p> <p>Outcome measurement</p> <p>Follow up is by postal questionnaire 90 days after randomisation, and data will be entered into the study database by a researcher blind to allocation. The primary outcome is the number of days spent at home (for those admitted from home), or days spent in the same care home (if admitted from a care home). Secondary outcomes include mortality, institutionalisation, health and social care resource use, and scaled outcome measures, including quality of life, disability, mental well-being. Carer strain and well being will also be measured at 90 days.</p> <p>Analyses</p> <p>Comparisons of outcomes and costs, and a cost utility analysis between the intervention and control groups will be carried out.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN21800480">ISRCTN21800480</a></p

Ultra-High Carrier Mobilities in Ferroelectric Domain Wall Corbino Cones at Room Temperature

Recently, electrically conducting heterointerfaces between dissimilar band-insulators (such as lanthanum aluminate and strontium titanate) have attracted considerable research interest. Charge transport has been thoroughly explored and fundamental aspects of conduction firmly established. Perhaps surprisingly, similar insights into conceptually much simpler conducting homointerfaces, such as the domain walls that separate regions of different orientations of electrical polarisation within the same ferroelectric band-insulator, are not nearly so well-developed. Addressing this disparity, we herein report magnetoresistance in approximately conical 180° charged domain walls, which occur in partially switched ferroelectric thin film single crystal lithium niobate. This system is ideal for such measurements: firstly, the conductivity difference between domains and domain walls is extremely and unusually large (a factor of at least 1013) and hence currents driven through the thin film, between planar top and bottom electrodes, are overwhelmingly channelled along the walls; secondly, when electrical contact is made to the top and bottom of the domain walls and a magnetic field is applied along their cone axes (perpendicular to the thin film surface), then the test geometry mirrors that of a Corbino disc, which is a textbook arrangement for geometric magnetoresistance measurement. Our data imply carriers at the domain walls with extremely high room temperature Hall mobilities of up to ~ 3,700cm2V-1s-1. This is an unparalleled value for oxide interfaces (and for bulk oxides too) and is most comparable to mobilities in other systems typically seen at cryogenic, rather than at room, temperature

Off-label Utilization of Antihypertensive Medications in Children

Objective— To examine off-label utilization and costs of antihypertensive drugs in children using a national sample of prescription claims. Design— Cross-sectional study. Setting— 2002 Medstat MarketScan Database, a national sample of outpatient prescription claims of children ≥18 years old enrolled in private, employer-sponsored health plans. Main Outcome Measures— Off-label use of antihypertensive drugs by patient age and costs of antihypertensives calculated as mean cost per child per 30-day fill. Results— One-half of the index antihypertensive prescription claims were off-label, based on minimum age criteria. Boys were more likely (56%) than girls (46%) to be prescribed off-label antihypertensives (p<0.001). Children aged ≥12 years were more likely to be prescribed off-label antihypertensives (53%) compared with children aged ≥5 (46%) and 6–11 years (42%, p<0.001). Off-label use varied significantly by class of antihypertensive drugs (p<0.001). Overall, off-label antihypertensives were significantly more expensive than on-label antihypertensives. Conclusions— Despite availability of often less expensive on-label alternatives for the same class of antihypertensive drugs, off-label antihypertensive drugs were prescribed frequently in children. These findings underscore the potential clinical and economic implications of common off-label prescribing, for children, their parents, physicians and payers. Originally published Ambulatory Pediatrics, Vol. 7, No. 4, July 200

Kepler eclipsing binary stars. VII. the catalogue of eclipsing binaries found in the entire Kepler data set

The primary Kepler Mission provided nearly continuous monitoring of ~200,000 objects with unprecedented photometric precision. We present the final catalog of eclipsing binary systems within the 105 deg2 Kepler field of view. This release incorporates the full extent of the data from the primary mission (Q0-Q17 Data Release). As a result, new systems have been added, additional false positives have been removed, ephemerides and principal parameters have been recomputed, classifications have been revised to rely on analytical models, and eclipse timing variations have been computed for each system. We identify several classes of systems including those that exhibit tertiary eclipse events, systems that show clear evidence of additional bodies, heartbeat systems, systems with changing eclipse depths, and systems exhibiting only one eclipse event over the duration of the mission. We have updated the period and galactic latitude distribution diagrams and included a catalog completeness evaluation. The total number of identified eclipsing and ellipsoidal binary systems in the Kepler field of view has increased to 2878, 1.3% of all observed Kepler targets

The SWELLS survey. III. Disfavouring "heavy" initial mass functions for spiral lens galaxies

We present gravitational lens models for 20 strong gravitational lens systems observed as part of the Sloan WFC Edge-on Late-type Lens Survey (SWELLS) project. Fifteen of the lenses are taken from paper I while five are newly discovered systems. The systems are galaxy-galaxy lenses where the foreground deflector has an inclined disc, with a wide range of morphological types, from late-type spiral to lenticular. For each system, we compare the total mass inside the critical curve inferred from gravitational lens modelling to the stellar mass inferred from stellar population synthesis (SPS) models, computing the stellar mass fraction f* = M(SPS)/M(lens). We find that, for the lower mass SWELLS systems, adoption of a Salpeter stellar initial mass function (IMF) leads to estimates of f* that exceed 1. This is unphysical, and provides strong evidence against the Salpeter IMF being valid for these systems. Taking the lower mass end of the SWELLS sample sigma(SIE) < 230 km/s, we find that the IMF is lighter (in terms of stellar mass-to-light ratio) than Salpeter with 98% probability, and consistent with the Chabrier IMF and IMFs between the two. This result is consistent with previous studies of spiral galaxies based on independent techniques. In combination with recent studies of massive early-type galaxies that have favoured a heavier Salpeter-like IMF, this result strengthens the evidence against a universal stellar IMF.Comment: Accepted for publication in MNRAS. Some changes (none major) to address the referee's comments. 18 pages, 8 figure

A cohort examination to establish reporting of the remit and function of Trial Steering Committees in randomised controlled trials

BACKGROUND: The DAMOCLES project established a widely used Data Monitoring Committee (DMC) Charter for randomised controlled trials (RCTs). Typically, within the UK, the DMC is advisory and recommends to another executive body; the Trial Steering Committee (TSC). Despite the executive role of the TSC, the CONSORT Statement does not explicitly require reporting of TSC activity, although is included as an example of good reporting. A lack of guidance on TSC reporting can impact transparency of trial oversight, ultimately leading to a misunderstanding regarding role and, subsequently, further variation in practice. This review aimed to establish reporting practice of TSC involvement in RCTs, and thus make recommendations for reporting. METHODS: A cohort examination identifying reporting practice was undertaken. The cohort comprised RCTs published in three leading medical journals (the British Medical Journal, The Lancet and the New England Journal of Medicine) within 6 months in 2012 and the full NIHR HTA Monograph series. Details of TSC constitution and impact were extracted from main publications and published supplements. RESULTS: Of 415 publications, 264 were eligible. These were typical in terms of trial design. Variations in reporting between journals and monographs was notable. TSC presence was identified in approximately half of trials (n = 144), of which 109 worked alongside a DMC. No publications justified not convening a TSC. When reported, the role of the committee and examples of impact in design, conduct and analysis were summarised. CONCLUSIONS: We present the first review of reporting TSC activity in the published academic literature. An absence of reporting standards with regards to TSC constitution, activity and impact on trial conduct was identified which can influence transparency of reporting trial oversight. Consistent reporting is vital for the benefits and impact of the TSC role to be understood to support adoption of this oversight structure and reduce global variations in practice