Munchausen by internet: current research and future directions.

The Internet has revolutionized the health world, enabling self-diagnosis and online support to take place irrespective of time or location. Alongside the positive aspects for an individual's health from making use of the Internet, debate has intensified on how the increasing use of Web technology might have a negative impact on patients, caregivers, and practitioners. One such negative health-related behavior is Munchausen by Internet

Using read-across to build physiologically-based kinetic models: Part 1. Development of a KNIME workflow to assist analogue selection for PBK modelling

Read-across refers to the process by which information from one (source) chemical is used to infer information about another similar (target) chemical. This method can be used to fill data gaps and so inform safety assessment where data are lacking for chemicals of interest. As one chemical cannot be considered as absolutely similar to another, only similar with respect to a given property, it is essential to justify the selection of similar chemicals (analogues) for the purposes of read-across. A previously created dataset of available physiologically-based kinetic (PBK) models (referred to as the PBK modelling dataset or PMD) was used in the development of a KNIME workflow. KNIME is a freely-available, open-source analytics platform that allows users to create workflows to analyse and visualise data. The KNIME workflow described here was designed to identify chemical analogues with a corresponding model in the PMD. The PMD combined with the KWAAS enables PBK model information from source chemical(s) to be used in a read-across approach to help develop new PBK models for target chemicals. This KNIME workflow was applied to six chemicals, representing different types of chemical classes (drugs, cosmetics, botanicals, industrial chemicals, pesticides, and food additives) to assess its applicability across various industries. Information acquired from these PBK models can be used to support safety assessment of chemicals and reduce reliance on animal testing

Using Read-Across to Build Physiologically-Based Kinetic Models: Part 2. Case Studies for atenolol and flumioxazin

Read-across, wherein information from a data-rich chemical is used to make a prediction for a similar chemical that lacks the relevant data, is increasingly being accepted as an alternative to animal testing. Identifying chemicals that can be considered as similar (analogues) is crucial to the process. Two resources have been developed previously to address the issue of analogue selection and facilitate physiologically-based kinetic (PBK) model development, using read-across. Chemical-specific PBK models, available in the literature, were collated to form a PBK model dataset (PMD) of over 7,500 models. A KNIME workflow was created to accompany this PMD that can aid the selection of appropriate chemical analogues from chemicals within this dataset (i.e. chemicals that are similar to a target of interest and are known to have an existing PBK model). Information from the PBK model for the source chemical can then be used in a read-across approach to inform the development of a new PBK model for the target. The application of these resources is tested here using two case studies (i) for the drug atenolol and (ii) for the plant protection product, flumioxazin. New PBK models were constructed for these two target chemicals using data obtained from source chemicals, identified by the workflow as being similar (analogues). In each case, the published PBK model for the source chemical was initially reproduced, as accurately as possible, before being adapted and used as a template for the target chemical. The performance of the new PBK models was assessed by comparing simulation outputs to existing data on key kinetic properties for the targets. The results demonstrate that a read-across approach can be successfully applied to develop new PBK models for data-poor chemicals, thus enabling their deployment during early-stage risk assessment. This assists prediction of internal exposure whilst reducing reliance on animal testing

A test of financial incentives to improve warfarin adherence

<p>Abstract</p> <p>Background</p> <p>Sub-optimal adherence to warfarin places millions of patients at risk for stroke and bleeding complications each year. Novel methods are needed to improve adherence for warfarin. We conducted two pilot studies to determine whether a lottery-based daily financial incentive is feasible and improves warfarin adherence and anticoagulation control.</p> <p>Methods</p> <p>Volunteers from the University of Pennsylvania Anticoagulation Management Center who had taken warfarin for at least 3 months participated in either a pilot study with a lottery with a daily expected value of $5 (N = 10) or a daily expected value of$3 (N = 10). All subjects received use of an Informedix Med-eMonitor™ System with a daily reminder feature. If subjects opened up their pill compartments appropriately, they were entered into a daily lottery with a 1 in 5 chance of winning $10 and a 1 in 100 chance of winning$100 (pilot 1) or a 1 in 10 chance of winning $10 and a 1 in 100 chance of winning$100 (pilot 2). The primary study outcome was proportion of incorrect warfarin doses. The secondary outcome was proportion of INR measurements not within therapeutic range. Within-subject pre-post comparisons were done of INR measurements with comparisons with either historic means or within-subject comparisons of incorrect warfarin doses.</p> <p>Results</p> <p>In the first pilot, the percent of out-of-range INRs decreased from 35.0% to 12.2% during the intervention, before increasing to 42% post-intervention. The mean proportion of incorrect pills taken during the intervention was 2.3% incorrect pills, compared with a historic mean of 22% incorrect pill taking in this clinic population. Among the five subjects who also had MEMS cap adherence data from warfarin use in our prior study, mean incorrect pill taking decreased from 26% pre-pilot to 2.8% in the pilot. In the second pilot, the time out of INR range decreased from 65.0% to 40.4%, with the proportion of mean incorrect pill taking dropping to 1.6%.</p> <p>Conclusion</p> <p>A daily lottery-based financial incentive demonstrated the potential for significant improvements in missed doses of warfarin and time out of INR range. Further testing should be done of this approach to determine its effectiveness and potential application to both warfarin and other chronic medications.</p

Star forming dwarf galaxies

Star forming dwarf galaxies (SFDGs) have a high gas content and low metallicities, reminiscent of the basic entities in hierarchical galaxy formation scenarios. In the young universe they probably also played a major role in the cosmic reionization. Their abundant presence in the local volume and their youthful character make them ideal objects for detailed studies of the initial stellar mass function (IMF), fundamental star formation processes and its feedback to the interstellar medium. Occasionally we witness SFDGs involved in extreme starbursts, giving rise to strongly elevated production of super star clusters and global superwinds, mechanisms yet to be explored in more detail. SFDGs is the initial state of all dwarf galaxies and the relation to the environment provides us with a key to how different types of dwarf galaxies are emerging. In this review we will put the emphasis on the exotic starburst phase, as it seems less important for present day galaxy evolution but perhaps fundamental in the initial phase of galaxy formation.Comment: To appear in JENAM Symposium "Dwarf Galaxies: Keys to Galaxy Formation and Evolution", P. Papaderos, G. Hensler, S. Recchi (eds.). Lisbon, September 2010, Springer Verlag, in pres

Exploring diurnal variation using piecewise linear splines:an example using blood pressure

Background: There are many examples of physiological processes that follow a circadian cycle and researchers are interested in alternative methods to illustrate and quantify this diurnal variation. Circadian blood pressure (BP) deserves additional attention given uncertainty relating to the prognostic significance of BP variability in relation to cardiovascular disease. However, the majority of studies exploring variability in ambulatory blood pressure monitoring (ABPM) collapse the data into single readings ignoring the temporal nature of the data. Advanced statistical techniques are required to explore complete variation over 24 h. Methods: We use piecewise linear splines in a mixed-effects model with a constraint to ensure periodicity as a novel application for modelling daily blood pressure. Data from the Mitchelstown Study, a cross-sectional study of Irish adults aged 47–73 years (n = 2047) was utilized. A subsample (1207) underwent 24-h ABPM. We compared patterns between those with and without evidence of subclinical target organ damage (microalbuminuria). Results: We were able to quantify the steepest rise and fall in SBP, which occurred just after waking (2.23 mmHg/30 min) and immediately after falling asleep (−1.93 mmHg/30 min) respectively. The variation about an individual’s trajectory over 24 h was 12.3 mmHg (standard deviation). On average those with microalbuminuria were found to have significantly higher SBP (7.6 mmHg, 95% CI 5.0–10.1) after adjustment for age, sex and BMI. Including an interaction term between each linear spline and microalbuminuria did not improve model fit. Conclusion: We have introduced a practical method for the analysis of ABPM where we can determine the rate of increase or decrease for different periods of the day. This may be particularly useful in examining chronotherapy effects of antihypertensive medication. It offers new measures of short-term BP variability as we can quantify the variation about an individual’s trajectory but also allows examination of the variation in slopes between individuals (random-effects)

Study on Phylogenetic Relationships, Variability, and Correlated Mutations in M2 Proteins of Influenza Virus A

M2 channel, an influenza virus transmembrane protein, serves as an important target for antiviral drug design. There are still discordances concerning the role of some residues involved in proton transfer as well as the mechanism of inhibition by commercial drugs. The viral M2 proteins show high conservativity; about 3/4 of the positions are occupied by one residue in over 95%. Nine M2 proteins from the H3N2 strain and possibly two proteins from H2N2 strains make a phylogenic cluster closely related to 2RLF. The variability range is limited to 4 residues/position with one exception. The 2RLF protein stands out by the presence of 2 serines at the positions 19 and 50, which are in most other M2 proteins occupied by cysteines. The study of correlated mutations shows that there are several positions with significant mutational correlation that have not been described so far as functionally important. That there are 5 more residues potentially involved in the M2 mechanism of action. The original software used in this work (Consensus Constructor, SSSSg, Corm, Talana) is freely accessible as stand-alone offline applications upon request to the authors. The other software used in this work is freely available online for noncommercial purposes at public services on bioinformatics such as ExPASy or NCBI. The study on mutational variability, evolutionary relationship, and correlated mutation presented in this paper is a potential way to explain more completely the role of significant factors in proton channel action and to clarify the inhibition mechanism by specific drugs

BH3-only proteins BIM and PUMA in the regulation of survival and neuronal differentiation of newly generated cells in the adult mouse hippocampus

Neurogenesis persists in the adult hippocampus, where several thousand neurons are born every day. Most of the newly generated cells are eliminated by apoptosis, possibly because of their failure to integrate properly into neural networks. The BH3-only proteins Bim and Puma have been shown to mediate trophic factor withdrawal- and anoikis-induced apoptosis in various systems. We therefore determined their impact on proliferation, survival, and differentiation of adult-generated cells in the mouse hippocampus using gene-deficient mice. Wild-type, bim-, and puma-deficient mice showed similar rates of precursor cell proliferation, as evidenced by 5-bromo-2-deoxyuridine (BrdU)-incorporation. Deficiency in either bim or puma significantly increased the survival of adult-born cells in the dentate gyrus (DG) after 7 days. Consistently, we detected increased numbers of doublecortin (DCX)-positive and fewer terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelled-positive cells in the DG of bim- and puma-deficient mice. Bim and puma deficiency did not change early markers of neuronal differentiation, as evidenced by BrdU/DCX double-labelling. However, BrdU/NeuN double-labelling revealed that deficiency of bim, but not puma, accelerated the differentiation of newly generated cells into a neuronal phenotype. Our data show that Bim and Puma are prominently involved in the regulation of neuronal progenitor cell survival in the adult DG, but also suggest that Bim has an additional role in neuronal differentiation of adult-born neural precursor cells

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Screening for psychological distress in patients with lung cancer: results of a clinical audit evaluating the use of the patient Distress Thermometer

Patients with lung cancer frequently suffer psychological distress and guidelines in the United Kingdom recommend screening of all cancer patients for this problem. The audit investigated use of the Distress Thermometer in terms of staff adherence to locally developed guidelines, patient willingness to use the tool, its impact on referral rates to clinical psychology services and concordance between the tool and the clinical assessment. Use of the Distress Thermometer was audited over a 3-month period in one lung cancer outpatient clinic. Referrals to clinical psychology services in response to clearly delineated referral indicators were assessed. Patient-reported outcomes were compared with practitioner assessment of need during clinical consultations to see whether the tool was measuring distress effectively. Thirty three of 34 patients used the Distress Thermometer during the audit period. Ten reported distress levels above 4 in the emotional or family problems domains. On ten occasions, the clinical interview identified problems not elicited by the Distress Thermometer. Guidelines were adhered to by staff, and patients were offered information about local support services and referral to clinical psychology services where indicated. Whilst all patients were happy to receive written information about further sources of support, none wanted to be referred to psychological services at that time. The Distress Thermometer is acceptable to patients with lung cancer in outpatient settings but it did not increase referrals for psychological support. Staff found it to be a useful tool in opening up communication about patient issues although it should not replace a comprehensive clinical interview