ACE inhibitor and angiotensin receptor-II antagonist prescribing and hospital admissions with acute kidney injury: A longitudinal ecological study

This is the final version. Available from the publisher via the DOI in this record.Background: ACE Inhibitors (ACE-I) and Angiotensin-Receptor Antagonists (ARAs) are commonly prescribed but can cause acute kidney injury (AKI) during intercurrent illness. Rates of hospitalization with AKI are increasing. We aimed to determine whether hospital AKI admission rates are associated with increased ACE-I/ARA prescribing. Methods and Findings: English NHS prescribing data for ACE-I/ARA prescriptions were matched at the level of the general practice to numbers of hospital admissions with a primary diagnosis of AKI. Numbers of prescriptions were weighted for the demographic characteristics of general practices by expressing prescribing as rates where the denominator is Age, Sex, and Temporary Resident Originated Prescribing Units (ASTRO-PUs). We performed a mixed-effect Poisson regression to model the number of admissions for AKI occurring in each practice for each of 4 years from 1/4/2007. From 2007/8-2010/11, crude AKI admission rates increased from 0.38 to 0.57 per 1000 patients (51.6% increase), and national annual ACE-I/ARA prescribing rates increased by 0.032 from 0.202 to 0.234 (15.8% increase). There was strong evidence (p<0.001) that increases in practice-level prescribing of ACE-I/ARA over the study period were associated with an increase in AKI admission rates. The increase in prescribing seen in a typical practice corresponded to an increase in admissions of approximately 5.1% (rate ratio = 1.051 for a 0.03 per ASTRO-PU increase in annual prescribing rate, 95%CI 1.047-1.055). Using the regression model we predict that 1,636 (95%CI 1,540-1,780) AKI admissions would have been avoided if prescribing rates were at the 2007/8 level, equivalent to 14.8% of the total increase in AKI admissions. Conclusion: In this ecological analysis, up to 15% of the increase in AKI admissions in England over a 4-year time period is potentially attributable to increased prescribing of ACE-I and ARAs. However, these findings are limited by the lack of patient level data such as indication for prescribing and patient characteristics. © 2013 Tomlinson et al.Cambridge Biomedical Research InstituteBritish Heart Foundatio

The accuracy of diagnostic coding for acute kidney injury in England - A single centre study

This is the final version. Available on open access from BMC via the DOI in this recordBackground: Acute kidney injury (AKI) is an independent risk factor for mortality and is responsible for a significant burden of healthcare expenditure, so accurate measurement of its incidence is important. Administrative coding data has been used for assessing AKI incidence, and shows an increasing proportion of hospital bed days attributable to AKI. However, the accuracy of coding for AKI and changes in coding over time have not been studied in England. Methods. We studied a random sample of admissions from 2005 and 2010 where ICD-10 code N17 (acute renal failure) was recorded in the administrative coding data at one acute NHS Foundation Trust in England. Using the medical notes and computerised records we examined the demographic and clinical details of these admissions. Results: Against a 6.3% (95% CI 4.8-7.9%) increase in all non-elective admissions, we found a 64% increase in acute renal failure admissions (95% CI 41%-92%, p<0.001) in 2010 compared to 2005. Median age was 78 years (IQR 72-87), 11-25% had a relevant pre-admission co-morbidity and 64% (55-73%) were taking drugs known to be associated with AKI. Over both years, 95% (91-99%) of cases examined met the Kidney Disease: Improving Global Outcomes criteria for AKI. Conclusions: Patients with hospital admissions where AKI has been coded are elderly with multiple co-morbidities. Our results demonstrate a high positive predictive value of coding data for a clinical diagnosis of AKI, with no suggestion of marked changes in coding of AKI between 2005 and 2010. © 2013 Tomlinson et al; licensee BioMed Central Ltd.Cambridge Biomedical Research InstituteBritish Heart Foundatio

Dodecahedral space topology as an explanation for weak wide-angle temperature correlations in the cosmic microwave background

Cosmology's standard model posits an infinite flat universe forever expanding under the pressure of dark energy. First-year data from the Wilkinson Microwave Anisotropy Probe (WMAP) confirm this model to spectacular precision on all but the largest scales (Bennett {\it et al.}, 2003 ; Spergel {\it et al.}, 2003). Temperature correlations across the microwave sky match expectations on scales narrower than $60^{\circ}$, yet vanish on scales wider than $60^{\circ}$. Researchers are now seeking an explanation of the missing wide-angle correlations (Contaldi {\it et al.}, 2003 ; Cline {\it et al.}, 2003). One natural approach questions the underlying geometry of space, namely its curvature (Efstathiou, 2003) and its topology (Tegmark {\it et al.}, 2003). In an infinite flat space, waves from the big bang would fill the universe on all length scales. The observed lack of temperature correlations on scales beyond $60^{\circ}$ means the broadest waves are missing, perhaps because space itself is not big enough to support them. Here we present a simple geometrical model of a finite, positively curved space -- the Poincar\'e dodecahedral space -- which accounts for WMAP's observations with no fine-tuning required. Circle searching (Cornish, Spergel and Starkman, 1998) may confirm the model's topological predictions, while upcoming Planck Surveyor data may confirm its predicted density of $\Omega_0 \simeq 1.013 > 1$. If confirmed, the model will answer the ancient question of whether space is finite or infinite, while retaining the standard Friedmann-Lema\^\i{}tre foundation for local physics.Comment: 10 pages, 4 figures. This is a slightly longer version of the paper published in Nature 425, p. 593, 200

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo

GU81, a VEGFR2 antagonist peptoid, enhances the anti-tumor activity of doxorubicin in the murine MMTV-PyMT transgenic model of breast cancer

<p>Abstract</p> <p>Background</p> <p>Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis under physiological and pathological conditions. Anti-VEGF therapy is a clinically proven strategy for the treatment of a variety of cancers including colon, breast, lung, and renal cell carcinoma. Since VEGFR2 is the dominant angiogenic signaling receptor, it has become an important target in the development of novel anti-angiogenic therapies. We have reported previously the development of an antagonistic VEGFR2 peptoid (GU40C4) that has promising anti-angiogenic activity <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>In the current study, we utilize a derivative of GU40C4, termed GU81 in therapy studies. GU81 was tested alone or in combination with doxorubicin for <it>in vivo </it>efficacy in the MMTV-PyMT transgenic model of breast cancer.</p> <p>Results</p> <p>The derivative GU81 has increased <it>in vitro </it>efficacy compared to GU40C4. Single agent therapy (doxorubicin or GU81 alone) had no effect on tumor weight, histology, tumor fat content, or tumor growth index. However, GU81 is able to significantly to reduce total vascular area as a single agent. GU81 used in combination with doxorubicin significantly reduced tumor weight and growth index compared to all other treatment groups. Furthermore, treatment with combination therapy significantly arrested tumor progression at the premalignant stage, resulting in increased tumor fat content. Interestingly, treatment with GU81 alone increased tumor-VEGF levels and macrophage infiltration, an effect that was abrogated when used in combination with doxorubicin.</p> <p>Conclusion</p> <p>This study demonstrates the VEGFR2 antagonist peptoid, GU81, enhances the anti-tumor activity of doxorubicin in spontaneous murine MMTV-PyMT breast tumors.</p

In-reach specialist nursing teams for residential care homes : uptake of services, impact on care provision and cost-effectiveness

Background: A joint NHS-Local Authority initiative in England designed to provide a dedicated nursing and physiotherapy in-reach team (IRT) to four residential care homes has been evaluated.The IRT supported 131 residents and maintained 15 'virtual' beds for specialist nursing in these care homes. Methods: Data captured prospectively (July 2005 to June 2007) included: numbers of referrals; reason for referral; outcome (e.g. admission to IRT bed, short-term IRT support); length of stay in IRT; prevented hospital admissions; early hospital discharges; avoided nursing home transfers; and detection of unrecognised illnesses. An economic analysis was undertaken. Results: 733 referrals were made during the 2 years (range 0.5 to 13.0 per resident per annum)resulting in a total of 6,528 visits. Two thirds of referrals aimed at maintaining the resident's independence in the care home. According to expert panel assessment, 197 hospital admissions were averted over the period; 20 early discharges facilitated; and 28 resident transfers to a nursing home prevented. Detection of previously unrecognised illnesses accounted for a high number of visits. Investment in IRT equalled £44.38 per resident per week. Savings through reduced hospital admissions, early discharges, delayed transfers to nursing homes, and identification of previously unrecognised illnesses are conservatively estimated to produce a final reduction in care cost of £6.33 per resident per week. A sensitivity analysis indicates this figure might range from a weekly overall saving of £36.90 per resident to a 'worst case' estimate of £2.70 extra expenditure per resident per week. Evaluation early in implementation may underestimate some cost-saving activities and greater savings may emerge over a longer time period. Similarly, IRT costs may reduce over time due to the potential for refinement of team without major loss in effectiveness. Conclusion: Introduction of a specialist nursing in-reach team for residential homes is at least cost neutral and, in all probability, cost saving. Further benefits include development of new skills in the care home workforce and enhanced quality of care. Residents are enabled to stay in familiar surroundings rather than unnecessarily spending time in hospital or being transferred to a higher dependency nursing home setting

Evaluation of skin dose associated with different frequencies of bolus applications in post-mastectomy three-dimensional conformal radiotherapy

<p>Abstract</p> <p>Background</p> <p>The study aimed to calculate chest-wall skin dose associated with different frequencies of bolus applications in post-mastectomy three-dimensional conformal radiotherapy (3D-CRT) and to provide detailed information in the selection of an appropriate bolus regimen in this clinical setting.</p> <p>Methods</p> <p>CT-Simulation scans of 22 post-mastectomy patients were used. Chest wall for clinical target volume (CTV) and a volume including 2-mm surface thickness of the chest wall for skin structures were delineated. Precise PLAN 2.11 treatment planning system (TPS) was used for 3D-CRT planning. 50 Gy in 25 fractions were prescribed using tangential fields and 6-MV photons. Six different frequencies of bolus applications (0, 5, 10, 15, 20, and 25) were administered. Cumulative dose-volume histograms were generated for each bolus regimen. The minimum, maximum and mean skin doses associated with the bolus regimens were compared. To test the accuracy of TPS dose calculations, experimental measurements were performed using EBT gafchromic films.</p> <p>Results</p> <p>The mean, minimum and maximum skin doses were significantly increased with increasing days of bolus applications (p < 0.001). The minimum skin doses for 0, 5, 10, 15, 20, and 25 days of bolus applications were 73.0% ± 2.0%, 78.2% ± 2.0%, 83.3% ± 1.7%, 88.3% ± 1.6%, 92.2% ± 1.7%, and 93.8% ± 1.8%, respectively. The minimum skin dose increments between 20 and 25 (1.6% ± 1.0%), and 15 and 20 (4.0% ± 1.0%) days of bolus applications were significantly lower than the dose increments between 0 and 5 (5.2% ± 0.6%), 5 and 10 (5.1% ± 0.8%), and 10 and 15 (4.9% ± 0.8%) days of bolus applications (p < 0.001). The maximum skin doses for 0, 5, 10, 15, 20, and 25 days of bolus applications were 110.1% ± 1.1%, 110.3% ± 1.1%, 110.5% ± 1.2%, 110.8% ± 1.3%, 111.2% ± 1.5%, and 112.2% ± 1.7%, respectively. The maximum skin dose increments between 20 and 25 (1.0% ± 0.6%), and 15 and 20 (0.4% ± 0.3%) days of bolus applications were significantly higher than the dose increments between 0 and 5 (0.2% ± 0.2%), 5 and 10 (0.2% ± 0.2%), and 10 and 15 (0.2% ± 0.2%) days of bolus applications (p ≤ 0.003). The TPS overestimated the near-surface dose 10.8% at 2-mm below the skin surface.</p> <p>Conclusion</p> <p>In post-mastectomy 3D-CRT, using a 1-cm thick bolus in up to 15 of the total 25 fractions increased minimum skin doses with a tolerable increase in maximum doses.</p

Veterans walk to beat back pain: study rationale, design and protocol of a randomized trial of a pedometer-based Internet mediated intervention for patients with chronic low back pain

<p>Abstract</p> <p>Background</p> <p>Chronic back pain is a significant problem worldwide and may be especially prevalent among patients receiving care in the U.S. Department of Veterans Affairs healthcare system. Back pain affects adults at all ages and is associated with disability, lost workplace productivity, functional limitations and social isolation. Exercise is one of the most effective strategies for managing chronic back pain. Yet, there are few clinical programs that use low cost approaches to help patients with chronic back pain initiate and maintain an exercise program.</p> <p>Methods/Design</p> <p>We describe the design and rationale of a randomized controlled trial to assess the efficacy of a pedometer-based Internet mediated intervention for patients with chronic back pain. The intervention uses an enhanced pedometer, website and e-community to assist these patients with initiating and maintaining a regular walking program with the primary aim of reducing pain-related disability and functional interference. The study specific aims are: 1) To determine whether a pedometer-based Internet-mediated intervention reduces pain-related functional interference among patients with chronic back pain in the short term and over a 12-month timeframe. 2) To assess the effect of the intervention on walking (measured by step counts), quality of life, pain intensity, pain related fear and self-efficacy for exercise. 3) To identify factors associated with a sustained increase in walking over a 12-month timeframe among patients randomized to the intervention.</p> <p>Discussion</p> <p>Exercise is an integral part of managing chronic back pain but to be effective requires that patients actively participate in the management process. This intervention is designed to increase activity levels, improve functional status and make exercise programs more accessible for a broad range of patients with chronic back pain.</p> <p>Trial Registration Number</p> <p>NCT00694018</p

Computational toxicology using the OpenTox application programming interface and Bioclipse

BACKGROUND: Toxicity is a complex phenomenon involving the potential adverse effect on a range of biological functions. Predicting toxicity involves using a combination of experimental data (endpoints) and computational methods to generate a set of predictive models. Such models rely strongly on being able to integrate information from many sources. The required integration of biological and chemical information sources requires, however, a common language to express our knowledge ontologically, and interoperating services to build reliable predictive toxicology applications. FINDINGS: This article describes progress in extending the integrative bio- and cheminformatics platform Bioclipse to interoperate with OpenTox, a semantic web framework which supports open data exchange and toxicology model building. The Bioclipse workbench environment enables functionality from OpenTox web services and easy access to OpenTox resources for evaluating toxicity properties of query molecules. Relevant cases and interfaces based on ten neurotoxins are described to demonstrate the capabilities provided to the user. The integration takes advantage of semantic web technologies, thereby providing an open and simplifying communication standard. Additionally, the use of ontologies ensures proper interoperation and reliable integration of toxicity information from both experimental and computational sources. CONCLUSIONS: A novel computational toxicity assessment platform was generated from integration of two open science platforms related to toxicology: Bioclipse, that combines a rich scriptable and graphical workbench environment for integration of diverse sets of information sources, and OpenTox, a platform for interoperable toxicology data and computational services. The combination provides improved reliability and operability for handling large data sets by the use of the Open Standards from the OpenTox Application Programming Interface. This enables simultaneous access to a variety of distributed predictive toxicology databases, and algorithm and model resources, taking advantage of the Bioclipse workbench handling the technical layers

Expectations and needs of patients with a chronic disease toward self-management and eHealth for self-management purposes

Background: Self-management is considered as an essential component of chronic care by primary care professionals. eHealth is expected to play an important role in supporting patients in their self-management. For effective implementation of eHealth it is important to investigate patients’ expectations and needs regarding self-management and eHealth. The objectives of this study are to investigate expectations and needs of people with a chronic condition regarding self-management and eHealth for self-management purposes, their willingness to use eHealth, and possible differences between patient groups regarding these topics. Methods: Five focus groups with people with diabetes (n = 14), COPD (n = 9), and a cardiovascular condition (n = 7) were conducted in this qualitative research. Separate focus groups were organized based on patients’ chronic condition. The following themes were discussed: 1) the impact of the chronic disease on patients’ daily life; 2) their opinions and needs regarding self-management; and 3) their expectations and needs regarding, and willingness to use, eHealth for self-management purposes. A conventional content analysis approach was used for coding. Results: Patient groups seem to differ in expectations and needs regarding self-management and eHealth for self-management purposes. People with diabetes reported most needs and benefits regarding self-management and were most willing to use eHealth, followed by the COPD group. People with a cardiovascular condition mentioned having fewer needs for self-management support, because their disease had little impact on their life. In all patient groups it was reported that the patient, not the care professional, should choose whether or not to use eHealth. Moreover, participants reported that eHealth should not replace, but complement personal care. Many participants reported expecting feelings of anxiety by doing measurement themselves and uncertainty about follow-up of deviant data of measurements. In addition, many participants worried about the implementation of eHealth being a consequence of budget cuts in care. Conclusion: This study suggests that aspects of eHealth, and the way in which it should be implemented, should be tailored to the patient. Patients’ expected benefits of using eHealth to support self-management and their perceived controllability over their disease seem to play an important role in patients’ willingness to use eHealth for self-management purposes