Access to primary care and the route of emergency admission to hospital: retrospective analysis of national hospital administrative data

BACKGROUND: The UK government is pursuing policies to improve primary care access, as many patients visit accident and emergency (A and E) departments after being unable to get suitable general practice appointments. Direct admission to hospital via a general practitioner (GP) averts A and E use, and may reduce total hospital costs. It could also enhance the continuity of information between GPs and hospital doctors, possibly improving healthcare outcomes. OBJECTIVE: To determine whether primary care access is associated with the route of emergency admission-via a GP versus via an A and E department. METHODS: Retrospective analysis of national administrative data from English hospitals for 2011-2012. Adults admitted in an emergency (unscheduled) for ≥1 night via a GP or an A and E department formed the study population. The measure of primary care access-the percentage of patients able to get a general practice appointment on their last attempt-was derived from a large, nationally representative patient survey. Multilevel logistic regression was used to estimate associations, adjusting for patient and admission characteristics. RESULTS: The analysis included 2 322 112 emergency admissions (81.9% via an A and E department). With a 5 unit increase in the percentage of patients able to get a general practice appointment on their last attempt, the adjusted odds of GP admission (vs A and E admission) was estimated to increase by 15% (OR 1.15, 95% CI 1.12 to 1.17). The probability of GP admission if ≥95% of appointment attempts were successful in each general practice was estimated to be 19.6%. This probability reduced to 13.6% when <80% of appointment attempts were successful. This equates to 139 673 fewer GP admissions (456 232 vs 316 559) assuming no change in the total number of admissions. Associations were consistent in direction across geographical regions of England. CONCLUSIONS: Among hospital inpatients admitted as an emergency, patients registered to more accessible general practices were more likely to have been admitted via a GP (vs an A and E department). This furthers evidence suggesting that access to general practice is related to use of emergency hospital services in England. The relative merits of the two admission routes remain unclear

Important Issues in Implementing Global networks

Global communication networks are used by multinational companies for instant access to information and communications. Many advantages can be obtained from implementing a global network; however, many challenges exist in designing and implementing a network that encompasses different countries. This article presents some key issues for the design and implementation of a global network

Structure of amyloid-β (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.

Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20-34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD

Search for radiative pumping lines of OH masers: I. The 34.6um absorption line towards 1612 MHz OH maser sources

The 1612 MHz hydroxyl maser in circumstellar envelopes has long been thought to be pumped by 34.6um photons. Only recently, the Infrared Space Observatory has made possible spectroscopic observations which enable the direct confirmation of this pumping mechanism in a few cases. To look for the presence of this pumping line, we have searched the Infrared Space Observatory Data Archive and found 178 spectra with data around 34.6um for 87 galactic 1612MHz masers. The analysis performed showed that the noise level and the spectral resolution of the spectra are the most important factors affecting the detection of the 34.6um absorption line. Only 5 objects from the sample (3 red supergiants and 2 galactic center sources) are found to show clear 34.6um absorption (all of them already known) while two additional objects only tentatively show this line. The 3 supergiants show similar pump rates and their masers might be purely radiatively pumped. The pump rates of OH masers in late type stars are found to be about 0.05, only 1/5 of the theoretical value of 0.25 derived by Elitzur (1992). We have also found 16 maser sources which, according to the analysis assuming Elitzur's pump rate, should show the 34.6 $\mu$m absorption line but do not. These non-detections can be tentatively explained by far-infrared photon pumping, clumpy nature of the OH masing region or a limb-filling emission effect in the OH shell.Comment: 11 pages, 8 figures, 3 table

Paclitaxel and CYC3, an aurora kinase A inhibitor, synergise in pancreatic cancer cells but not bone marrow precursor cells.

BACKGROUND: Amplification of aurora kinase A (AK-A) overrides the mitotic spindle assembly checkpoint, inducing resistance to taxanes. RNA interference targeting AK-A in human pancreatic cancer cell lines enhanced taxane chemosensitivity. In this study, a novel AK-A inhibitor, CYC3, was investigated in pancreatic cancer cell lines, in combination with paclitaxel. METHODS: Western blot, flow cytometry and immunostaining were used to investigate the specificity of CYC3. Sulforhodamine B staining, time-lapse microscopy and colony-formation assays were employed to evaluate the cytotoxic effect of CYC3 and paclitaxel. Human colony-forming unit of granulocyte and macrophage (CFU-GM) cells were used to compare the effect in tumour and normal tissue. RESULTS: CYC3 was shown to be a specific AK-A inhibitor. Three nanomolar paclitaxel (growth inhibition 50% (GI(50)) 3 nM in PANC-1, 5.1 nM in MIA PaCa-2) in combination with 1 μM CYC3 (GI(50) 1.1 μM in MIA PaCa2 and 2 μM in PANC-1) was synergistic in inhibiting pancreatic cell growth and causing mitotic arrest, achieving similar effects to 10-fold higher concentrations of paclitaxel (30 nM). In CFU-GM cells, the effect of the combination was simply additive, displaying significantly less myelotoxicity compared with high concentrations of paclitaxel (30 nM; 60-70% vs 100% inhibition). CONCLUSION: The combination of lower doses of paclitaxel and CYC3 merits further investigation with the potential for an improved therapeutic index in vivo

Discrete Source Survey of 6 GHz OH emission from PNe & pPNe and first 6 GHz images of K 3-35

The aim of this study is to investigate the physical properties of molecular envelopes of planetary nebulae in their earliest stages of evolution. Using the 100m telescope at Effelsberg, we have undertaken a high sensitivity discrete source survey for the first excited state of OH maser emission (J=5/2, 2PI3/2 at 6GHz) in the direction of planetary and proto-planetary nebulae exhibiting 18cm OH emission (main and/or satellite lines), and we further validate our detections using the Nan\c{c}ay radio telescope at 1.6-1.7GHz and MERLIN interferometer at 1.6-1.7 and 6GHz. Two sources have been detected at 6035MHz (5cm), both of them are young (or very young) planetary nebulae. The first one is a confirmation of the detection of a weak 6035MHz line in Vy 2-2. The second one is a new detection, in K 3-35, which was already known to be an exceptional late type star because it exhibits 1720MHz OH emission. The detection of 6035MHz OH maser emission is confirmed by subsequent observations made with the MERLIN interferometer. These lines are very rarely found in evolved stars. The 1612MHz masers surround but are offset from the 1720 and 6035MHz masers which in turn lie close to a compact 22GHz continuum source embedded in the optical nebula.Comment: 9 pages, 7 figures, published in A&

Invasive fungal disease in PICU: epidemiology and risk factors

Candida and Aspergillus spp. are the most common agents responsible for invasive fungal infections in children. They are associated with a high mortality and morbidity rate as well as high health care costs. An important increase in their incidence has been observed during the past two decades. In infants and children, invasive candidiasis is five times more frequent than invasive aspergillosis. Candida sp. represents the third most common agent found in healthcare-associated bloodstream infections in children. Invasive aspergillosis is more often associated with hematological malignancies and solid tumors. Recommendations concerning prophylactic treatment for invasive aspergillosis have been recently published by the Infectious Diseases Society of America. Candida albicans is the main Candida sp. associated with invasive candidiasis in children, even if a strong trend toward the emergence of Candida non-albicans has been observed. The epidemiology and the risk factors for invasive fungal infections are quite different if considering previously healthy children hospitalized in the pediatric intensive care unit, or children with a malignancy or a severe hematological disease (leukemia). In children, the mortality rate for invasive aspergillosis is 2.5 to 3.5 higher than for invasive candidiasis (respectively 70% vs. 20% and 30%)

OH spectral evolution of oxygen-rich late-type stars

We investigated the main-line spectral evolution with shell thickness of oxygen rich AGB stars. The study is based on a sample of 30 sources distributed along the IRAS colour-colour diagram. The sources were chosen to trace the Miras with thick shells and the whole range of OH/IR stars. The Miras exhibit a 1665 MHz emission strength comparable to that at 1667 MHz. Even though the Miras of the study have quite thick shells, their spectral characteristics in both main lines attest to a strong heterogeneity in their OH shell with, in particular, the presence of significant turbulence and acceleration. The expansion velocity has been found to be about the same at 1665 and 1667 MHz, taking into account a possible velocity turbulence of 1-2km/s at the location of the main-line maser emission. An increase in the intensity ratio 1667/1665 with shell thickness has been found. A plausible explanation for such a phenomenon is that competitive gain in favour of the 1667 MHz line increases when the shell is getting thicker. There is an evolution in the spectral profile shape with the appearance of a substantial inter-peak signal when the shell is getting thicker. Also, inter-peak components are found and can be as strong as the external standard peaks when the shell is very thick. This trend for an increase of the signal in between the two main peaks is thought to be the result of an increase of the saturation with shell thickness. All sources but two - a Mira and an OH/IR star from the lower part of the colour-colour diagram - are weakly polarized. The strong polarization observed for those two particular objects is thought to be the result of perturbations in their shells.Comment: 19 pages, 12 figures, accepted for publication in A&

Timely HAART initiation may pave the way for a better viral control

<p>Abstract</p> <p>Background</p> <p>When to initiate antiretroviral therapy in HIV infected patients is a diffcult clinical decision. Actually, it is still a matter of discussion whether early highly active antiretroviral therapy (HAART) during primary HIV infection may influence the dynamics of the viral rebound, in case of therapy interruption, and overall the main disease course.</p> <p>Methods</p> <p>In this article we use a computational model and clinical data to identify the role of HAART timing on the residual capability to control HIV rebound after treatment suspension. Analyses of clinical data from three groups of patients initiating HAART respectively before seroconversion (very early), during the acute phase (early) and in the chronic phase (late), evidence differences arising from the very early events of the viral infection.</p> <p>Results</p> <p>The computational model allows a fine grain assessment of the impact of HAART timing on the disease outcome, from acute to chronic HIV-1 infection. Both patients' data and computer simulations reveal that HAART timing may indeed affect the HIV control capability after treatment discontinuation. In particular, we find a median time to viral rebound that is significantly longer in very early than in late patients.</p> <p>Conclusions</p> <p>A timing threshold is identified, corresponding to approximately three weeks post-infection, after which the capability to control HIV replication is lost. Conversely, HAART initiation occurring within three weeks from the infection could allow to preserve a significant control capability. This time could be related to the global triggering of uncontrolled immune activation, affecting residual immune competence preservation and HIV reservoir establishment.</p

A broad distribution of the alternative oxidase in microsporidian parasites

Microsporidia are a group of obligate intracellular parasitic eukaryotes that were considered to be amitochondriate until the recent discovery of highly reduced mitochondrial organelles called mitosomes. Analysis of the complete genome of Encephalitozoon cuniculi revealed a highly reduced set of proteins in the organelle, mostly related to the assembly of ironsulphur clusters. Oxidative phosphorylation and the Krebs cycle proteins were absent, in keeping with the notion that the microsporidia and their mitosomes are anaerobic, as is the case for other mitosome bearing eukaryotes, such as Giardia. Here we provide evidence opening the possibility that mitosomes in a number of microsporidian lineages are not completely anaerobic. Specifically, we have identified and characterized a gene encoding the alternative oxidase (AOX), a typically mitochondrial terminal oxidase in eukaryotes, in the genomes of several distantly related microsporidian species, even though this gene is absent from the complete genome of E. cuniculi. In order to confirm that these genes encode functional proteins, AOX genes from both A. locustae and T. hominis were over-expressed in E. coli and AOX activity measured spectrophotometrically using ubiquinol-1 (UQ-1) as substrate. Both A. locustae and T. hominis AOX proteins reduced UQ-1 in a cyanide and antimycin-resistant manner that was sensitive to ascofuranone, a potent inhibitor of the trypanosomal AOX. The physiological role of AOX microsporidia may be to reoxidise reducing equivalents produced by glycolysis, in a manner comparable to that observed in trypanosome