Informing thresholds for paediatric transfusion in Africa: the need for a trial [version 2; peer review: 2 approved]

Background: Owing to inadequate supplies of donor blood for transfusion in sub-Saharan Africa (sSA) World Health Organization paediatric guidelines recommend restrictive transfusion practices, based on expert opinion. We examined whether survival amongst hospitalised children by admission haemoglobin and whether this was influenced by malaria infection and/or transfusion. Methods: A retrospective analysis of standardised clinical digital records in an unselected population of children admitted to a rural hospital in Kenya over an 8-year period. We describe baseline parameters with respect to categories of anaemia and outcome (in-hospital death) by haemoglobin (Hb), malaria and transfusion status. Results: Among 29,226 children, 1,143 (3.9%) had profound anaemia (Hb <4g/dl) and 3,469 (11.9%) had severe anaemia (Hb 4-6g/d). In-hospital mortality rate was 97/1,143 (8.5%) if Hb<4g/dl or 164/2,326 (7.1%) in those with severe anaemia (Hb ≥4.0-<6g/dl). Admission Hb <3g/dl was associated with higher risk of death versus those with higher Hbs (OR=2.41 (95%CI: 1.8 - 3.24; P<0.001), increasing to OR=6.36, (95%CI: 4.21-9.62; P<0.001) in malaria positive children. Conversely, mortality in non-malaria admissions was unrelated to Hb level. Transfusion was associated with a non-significant improvement in outcome if Hb<3g/dl (malaria-only) OR 0.72 (95%CI 0.29 - 1.78), albeit the number of cases were too few to show a statistical difference. For those with Hb levels above 4g/dl, mortality was significantly higher in those receiving a transfusion compared to the non-transfused group. For non-malarial cases, transfusion did not affect survival-status, irrespective of baseline Hb level compared to children who were not transfused at higher Hb levels. Conclusion: Although severe anaemia is common among children admitted to hospital in sSA (~16%), our data do not indicate that outcome is improved by transfusion irrespective of malaria status. Given the limitations of observational studies, clinical trials investigating the role of transfusion in outcomes in children with severe anaemia are warranted

Survival and haematological recovery of children with severe malaria transfused in accordance to WHO guidelines in Kilifi, Kenya

Background: Severe anaemia requiring emergency blood transfusion is a common complication of malaria in children. To ensure access for urgent blood transfusion, the World Health Organization has developed clear guidelines with haemoglobin thresholds prevent unwarranted transfusion,. Few studies have reported outcome and haematological recovery of children with severe malaria where transfusion practice complies with WHO recommendations. Methods: A prospective observational study of survivors of severe and complicated malaria transfused in accordance with WHO guidelines. Children were invited for review at one month post-discharge. Non-attendees were traced in the community to ascertain survival. Results: Outcome was assessed in 213 survivors. Those transfused were younger, had a higher base deficit, mean lactate levels and a higher prevalence of respiratory distress. As expected mean admission haemoglobin (Hb) was significantly lower amongst transfused [5.0 g/dL SD: 1.9] compared to non-transfused children [8.3 g/dL SD: 1.7] (p < 0.001). At discharge mean Hb was similar 6.4 g/dL [SD: 1.5] and 6.8 g/dL [SD: 1.6] respectively (p = 0.08), most children remained moderately to severely anaemic. At one month follow up 166 children (78%) returned, in whom we found no differences in mean Hb between the transfused (10.2 g/dL [SD: 1.7]) and non-transfused (10.0 g/dL [SD: 1.3]) survivors ( p = 0.25). The major factors affecting haematological recovery were young age (< 24 months) and concomitant malaria parasitaemia; Hb being 8.8 g/dL [SD: 1.5] in parasitaemic individuals compared with 10.5 g/dL [SD: 1.3] in those without (p < 0.001). Conclusion: This data supports the policy of rational use of blood transfusion, as proposed in the WHO guidelines, for children with anaemia in areas where access to emergency transfusion is not guaranteed. We have provided empirical data indicating that transfusion does not influence superior recovery in haemoglobin concentrations and therefore cannot be justified on this basis alone. This may help resolve the disparity between international policy and current clinical practice. Effective anti- malarial treatment at discharge may prevent reoccurrence of anaemia

Overexpression of an endogenous type 2 diacylglycerol acyltransferase in the marine diatom Phaeodactylum tricornutum enhances lipid production and omega-3 long-chain polyunsaturated fatty acid content

Background: Oleaginous microalgae represent a valuable resource for the production of high-value molecules. Considering the importance of omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) for human health and nutrition the yields of high-value eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) require significant improvement to meet demand; however, the current cost of production remains high. A promising approach is to metabolically engineer strains with enhanced levels of triacylglycerols (TAGs) enriched in EPA and DHA. Results: Recently, we have engineered the marine diatom Phaeodactylum tricornutum to accumulate enhanced levels of DHA in TAG. To further improve the incorporation of omega-3 LC-PUFAs in TAG, we focused our effort on the identification of a type 2 acyl-CoA:diacylglycerol acyltransferase (DGAT) capable of improving lipid production and the incorporation of DHA in TAG. DGAT is a key enzyme in lipid synthesis. Following a diatom based in vivo screen of candidate DGATs, a native P. tricornutum DGAT2B was taken forward for detailed characterisation. Overexpression of the endogenous P. tricornutum DGAT2B was confirmed by qRT-PCR and the transgenic strain grew successfully in comparison to wildtype. PtDGAT2B has broad substrate specificity with preferences for C16 and LC-PUFAs acyl groups. Moreover, the overexpression of an endogenous DGAT2B resulted in higher lipid yields and enhanced levels of DHA in TAG. Furthermore, a combined overexpression of the endogenous DGAT2B and ectopic expression of a Δ5-elongase showed how iterative metabolic engineering can be used to increase DHA and TAG content, irrespective of nitrogen treatment. Conclusion: This study provides further insight into lipid metabolism in P. tricornutum and suggests a metabolic engineering approach for the efficient production of EPA and DHA in microalgae

High level accumulation of EPA and DHA in field-grown transgenic Camelina – a multi-territory evaluation of TAG accumulation and heterogeneity

The transgene-directed accumulation of non-native omega-3 long chain polyunsaturated fatty acids in the seed oil of Camelina sativa (Camelina) was evaluated in the field, in distinct geographical and regulatory locations. A construct, DHA2015.1, containing an optimal combination of biosynthetic genes, was selected for experimental field release in the UK, USA and Canada, and the accumulation of eicosapentaenoic acid and docosahexaenoic acid determined. The occurrence of these fatty acids in different triacylglycerol species was monitored and found to follow a broad trend irrespective of the agricultural environment. This is a clear demonstration of the stability and robust nature of the transgenic trait for omega-3 long chain polyunsaturated fatty acids in Camelina. Examination of nonseed tissues for the unintended accumulation of EPA and DHA failed to identify their presence in leaf, stem, flower, anther or capsule shell material, confirming the seed-specific accumulation of these novel fatty acids. Collectively these data confirm the promise of GM plant-based sources of so called omega-3 fish oils as a sustainable replacement for oceanically-derived oils

HST/FOS Eclipse Observations of the Nova-like Cataclysmic Variable UX Ursae Majoris

[abridged abstract] We present and analyze Hubble Space Telescope observations of the eclipsing nova-like cataclysmic variable UX UMa obtained with the Faint Object Spectrograph. Two eclipses each were observed with the G160L grating (covering the ultraviolet waveband) in August of 1994 and with the PRISM (covering the near-ultraviolet to near-infrared) in November of the same year. The system was 50% brighter in November than in August, which, if due to a change in the accretion rate, indicates a fairly substantial increase in Mdot_acc by >~ 50%. Model disk spectra constructed as ensembles of stellar atmospheres provide poor descriptions of the observed post-eclipse spectra, despite the fact that UX UMa's light should be dominated by the disk at this time. Suitably scaled single temperature model stellar atmospheres with T_eff = 12,500-14,500 K actually provide a better match to both the ultraviolet and optical post-eclipse spectra. Evidently, great care must be taken in attempts to derive accretion rates from comparisons of disk models to observations. One way to reconcile disk models with the observed post-eclipse spectra is to postulate the presence of a significant amount of optically thin material in the system. Such an optically thin component might be associated with the transition region (``chromosphere'') between the disk photosphere and the fast wind from the system, whose presence has been suggested by Knigge & Drew (1997).Comment: 35 pages, including 12 figures; to appear in the ApJ (Vol. 499

Autistic people’s perspectives on stereotypes: An interpretative phenomenological analysis

Autism stereotypes can often portray autistic people in a negative way. However, few studies have looked at how autistic people think they are perceived by others, and none have specifically asked autistic people what they think the autistic stereotypes are. Semi-structured interviews with twelve autistic adults (aged between 20-63 years) were conducted. Using Interpretative Phenomenological Analysis, three main themes emerged from the data. These were: (1) primary stereotype is that autistic people are ‘weird’; (2) autistic stereotypes have negative effects and consequences; (3) autistic people are heterogeneous. This study makes an important and novel contribution to understanding the experience of being autistic in several ways by exploring how autistic people feel they are perceived by others and identifying some of the ways in which negative stereotypes are believed to have negative consequences for autistic people

LOFAR Sparse Image Reconstruction

Context. The LOw Frequency ARray (LOFAR) radio telescope is a giant digital phased array interferometer with multiple antennas distributed in Europe. It provides discrete sets of Fourier components of the sky brightness. Recovering the original brightness distribution with aperture synthesis forms an inverse problem that can be solved by various deconvolution and minimization methods Aims. Recent papers have established a clear link between the discrete nature of radio interferometry measurement and the "compressed sensing" (CS) theory, which supports sparse reconstruction methods to form an image from the measured visibilities. Empowered by proximal theory, CS offers a sound framework for efficient global minimization and sparse data representation using fast algorithms. Combined with instrumental direction-dependent effects (DDE) in the scope of a real instrument, we developed and validated a new method based on this framework Methods. We implemented a sparse reconstruction method in the standard LOFAR imaging tool and compared the photometric and resolution performance of this new imager with that of CLEAN-based methods (CLEAN and MS-CLEAN) with simulated and real LOFAR data Results. We show that i) sparse reconstruction performs as well as CLEAN in recovering the flux of point sources; ii) performs much better on extended objects (the root mean square error is reduced by a factor of up to 10); and iii) provides a solution with an effective angular resolution 2-3 times better than the CLEAN images. Conclusions. Sparse recovery gives a correct photometry on high dynamic and wide-field images and improved realistic structures of extended sources (of simulated and real LOFAR datasets). This sparse reconstruction method is compatible with modern interferometric imagers that handle DDE corrections (A- and W-projections) required for current and future instruments such as LOFAR and SKAComment: Published in A&A, 19 pages, 9 figure

Dispersing the Mists: An Experimental History of Medicine Study into the Quality of Volatile Inhalations

This document is the Accepted Manuscript version. The final publication is available from Mary Ann Liebert, Inc. Publishers at https://doi.org/10.1089/jamp.2016.1357.Background: Dr. Nelson's Improved Inhaler was first marketed with an advertisement in The Lancet in 1865. Revolutionary at the time for its ease of use and patient-friendliness, the inhaler is still in use for self-treatment by many all over the world. On the occasion of its 150th anniversary, this study reports an experimental historical medicine approach to identify evidence for the quality of vapor inhalers. Methods: Through accessing reviews of the device's use by the contemporary medical establishment, it was established that Dr. Nelson's Inhaler enjoyed a reputation of quality and efficacy among reputable physicians generating empirical evidence of clinical performance. There was a general absence of product performance tests during this period. Therefore, modern inhalation performance testing was applied to test the aerosol delivery performance for Friars' Balsam, and its key chemical constituent, benzoic acid (BA). Results: A respirable dose of 59.9 ± 9.0 μg of BA was aerosolized in a 10 minutes period from a dose of 3.3 mL Friars' Balsam (equivalent to 35.1 ± 0.2 mg of BA) in 375 mL of steaming water using the glass twin stage impinger at a flow rate of 60 L·min−1. The respirable dose from a standardized aqueous BA inhalation formulation increased from 115.9 ± 10.6 to 200.2 ± 19.9 μg by increasing the simulated inhalation period from 5 to 10 minutes. When tested with a simulated inhalation maneuver (500 mL tidal volume, 13 minutes−1 respiration rate, 1:2 inspiratory:expiratory ratio) a respirable dose of 112.8 ± 40.3 μg was produced. Conclusions: This work has highlighted the potential for aerosol drug delivery using steam inhalers that are popular with patients. Physicians should therefore be aware of the potential for lung dosing with irritants when patients self-medicate using the Nelson Inhaler with vaporizing formulations such as Friars' Balsam.Peer reviewedFinal Accepted Versio

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of &lt; 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age &lt; 3 or &gt; 10 years (11% v 3% and 33% v 23%, respectively; P &lt; .001) and with longer symptom duration ( P &lt; .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials