Combination of (M)DSC and surface analysis to study the phase behaviour and drug distribution of ternary solid dispersions

Purpose: Miscibility of the different compounds that make up a solid dispersion based formulation play a crucial role in the drug release profile and physical stability of the solid dispersion as it defines the phase behaviour of the dispersion. The standard technique to obtain information on phase behaviour of a sample is (modulated) differential scanning calorimetry ((M)DSC). However, for ternary mixtures (M)DSC alone is not sufficient to characterize their phase behaviour and to gain insight into the distribution of the active pharmaceutical ingredient (API) in a two-phased polymeric matrix. Methods: MDSC was combined with complementary surface analysis techniques, specifically time-of-flight secondary ion mass spectrometry (ToF-SIMS) and atomic force microscopy (AFM). Three spray-dried model formulations with varying API/PLGA/PVP ratios were analyzed. Results: The distribution of the API in the ternary solid dispersions depended on formulation parameters. The extent of API surface coverage and therefore the distribution of the API over both polymeric phases differed significantly for the three formulations. Conclusions: Combining (M)DSC and surface analysis rendered additional insights in the composition of mixed phases in complex systems, like ternary solid dispersions

Fine-mapping of genetic loci driving spontaneous clearance of hepatitis C virus infection

Approximately three quarters of acute hepatitis C (HCV) infections evolve to a chronic state, while one quarter are spontaneously cleared. Genetic predispositions strongly contribute to the development of chronicity. We have conducted a genome-wide association study to identify genomic variants underlying HCV spontaneous clearance using ImmunoChip in European and African ancestries. We confrmed two previously reported signifcant associations, in the IL28B/IFNL4 and the major histocompatibility complex (MHC) regions, with spontaneous clearance in the European population. We further fne-mapped the association in the MHC to a region of about 50 kilo base pairs, down from 1 mega base pairs in the previous study. Additional analyses suggested that the association in MHC is stronger in samples from North America than those from Europe

Changing Place of Death in Children who died after discharge from Paediatric Intensive Care Units : a national, data linkage study

Background: Although child mortality is decreasing, more than half of all deaths in childhood occur in children with a life-limiting condition whose death may be expected. Aim: To assess trends in place of death and identify characteristics of children who died in the community after discharge from paediatric intensive care unit. Design: National data linkage study. Setting/participants: All children resident in England and Wales when admitted to a paediatric intensive care unit in the United Kingdom (1 January 2004 and 31 December 2014) were identified in the Paediatric Intensive Care Audit Network dataset. Linkage to death certificate data was available up to the end of 2014. Place of death was categorised as hospital (hospital or paediatric intensive care unit) or community (hospice, home or other) for multivariable logistic modelling. Results: The cohort consisted of 110,328 individuals. In all, 7709 deaths occurred after first discharge from paediatric intensive care unit. Among children dying, the percentage in-hospital at the time of death decreased from 83.8% in 2004 to 68.1% in 2014; 852 (0.8%) of children were discharged to palliative care. Children discharged to palliative care were eight times more likely to die in the community than children who died and had not been discharged to palliative care (odds ratio = 8.06 (95% confidence interval = 6.50–10.01)). Conclusions: The proportion of children dying in hospital is decreasing, but a large proportion of children dying after discharge from paediatric intensive care unit continue to die in hospital. The involvement of palliative care at the point of discharge has the potential to offer choice around place of care and death for these children and families

Shotgun Proteomics Identifies Serum Fibronectin as a Candidate Diagnostic Biomarker for Inclusion in Future Multiplex Tests for Ectopic Pregnancy

Ectopic pregnancy (EP) is difficult to diagnose early and accurately. Women often present at emergency departments in early pregnancy with a 'pregnancy of unknown location' (PUL), and diagnosis and exclusion of EP is challenging due to a lack of reliable biomarkers. The objective of this study was to identify novel diagnostic biomarkers for EP. Shotgun proteomics, incorporating combinatorial-ligand library pre-fractionation, was used to interrogate pooled sera (n = 40) from women undergoing surgery for EP, termination of viable intrauterine pregnancy and management of non-viable intrauterine pregnancy. Western blot was used to validate results in individual sera. ELISAs were developed to interrogate sera from women with PUL (n = 120). Sera were collected at time of first symptomatic presentation and categorized according to pregnancy outcome. The main outcome measures were differences between groups and area under the receiver operating curve (ROC). Proteomics identified six biomarker candidates. Western blot detected significant differences in levels of two of these candidates. ELISA of sera from second cohort revealed that these differences were only significant for one of these candidates, fibronectin. ROC analysis of ability of fibronectin to discriminate EP from other pregnancy outcomes suggested that fibronectin has diagnostic potential (ROC 0.6439; 95% CI 0.5090 to 0.7788; P>0.05), becoming significant when 'ambiguous' medically managed PUL excluded from analysis (ROC 0.6538; 95% CI 0.5158 to 0.7918; P<0.05). Fibronectin may make a useful adjunct to future multiplex EP diagnostic tests

A meta-analysis of long-term effects of conservation agriculture on maize grain yield under rain-fed conditions

Conservation agriculture involves reduced tillage, permanent soil cover and crop rotations to enhance soil fertility and to supply food from a dwindling land resource. Recently, conservation agriculture has been promoted in Southern Africa, mainly for maize-based farming systems. However, maize yields under rain-fed conditions are often variable. There is therefore a need to identify factors that influence crop yield under conservation agriculture and rain-fed conditions. Here, we studied maize grain yield data from experiments lasting 5 years and more under rain-fed conditions. We assessed the effect of long-term tillage and residue retention on maize grain yield under contrasting soil textures, nitrogen input and climate. Yield variability was measured by stability analysis. Our results show an increase in maize yield over time with conservation agriculture practices that include rotation and high input use in low rainfall areas. But we observed no difference in system stability under those conditions. We observed a strong relationship between maize grain yield and annual rainfall. Our meta-analysis gave the following findings: (1) 92% of the data show that mulch cover in high rainfall areas leads to lower yields due to waterlogging; (2) 85% of data show that soil texture is important in the temporal development of conservation agriculture effects, improved yields are likely on well-drained soils; (3) 73% of the data show that conservation agriculture practices require high inputs especially N for improved yield; (4) 63% of data show that increased yields are obtained with rotation but calculations often do not include the variations in rainfall within and between seasons; (5) 56% of the data show that reduced tillage with no mulch cover leads to lower yields in semi-arid areas; and (6) when adequate fertiliser is available, rainfall is the most important determinant of yield in southern Africa. It is clear from our results that conservation agriculture needs to be targeted and adapted to specific biophysical conditions for improved impact

Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P value = 4.9 × 10−04) and rs8099917 (P value = 5.5 × 10−04). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 3.6 × 10−05). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P value = 1.8 × 10−04). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917

The Renin-Angiotensin-Aldosterone system in patients with depression compared to controls – a sleep endocrine study

BACKGROUND: Hypercortisolism as a sign of hypothamamus-pituitary-adrenocortical (HPA) axis overactivity and sleep EEG changes are frequently observed in depression. Closely related to the HPA axis is the renin-angiotensin-aldosterone system (RAAS) as 1. adrenocorticotropic hormone (ACTH) is a common stimulus for cortisol and aldosterone, 2. cortisol release is suppressed by mineralocorticoid receptor (MR) agonists 3. angiotensin II (ATII) releases CRH and vasopressin from the hypothalamus. Furthermore renin and aldosterone secretion are synchronized to the rapid eyed movement (REM)-nonREM cycle. METHODS: Here we focus on the difference of sleep related activity of the RAAS between depressed patients and healthy controls. We studied the nocturnal plasma concentration of ACTH, cortisol, renin and aldosterone, and sleep EEG in 7 medication free patients with depression (1 male, 6 females, age: (mean +/-SD) 53.3 ± 14.4 yr.) and 7 age matched controls (2 males, 5 females, age: 54.7 ± 19.5 yr.). After one night of accommodation a polysomnography was performed between 23.00 h and 7.00 h. During examination nights blood samples were taken every 20 min between 23.00 h and 7.00 h. Area under the curve (AUC) for the hormones separated for the halves of the night (23.00 h to 3.00 h and 3.00 h to 7.00 h) were used for statistical analysis, with analysis of co variance being performed with age as a covariate. RESULTS: No differences in ACTH and renin concentrations were found. For cortisol, a trend to an increase was found in the first half of the night in patients compared to controls (p < 0.06). Aldosterone was largely increased in the first (p < 0.05) and second (p < 0.01) half of the night. Cross correlations between hormone concentrations revealed that in contrast to earlier findings, which included only male subjects, in our primarily female sample, renin and aldosterone secretion were not coupled and no difference between patients and controls could be found, suggesting a gender difference in RAAS regulation. No difference in conventional sleep EEG parameters were found in our sample. CONCLUSION: Hyperaldosteronism could be a sensitive marker for depression. Further our findings point to an altered renal mineralocorticoid sensitivity in patients with depression

The Formation of the First Massive Black Holes

Supermassive black holes (SMBHs) are common in local galactic nuclei, and SMBHs as massive as several billion solar masses already exist at redshift z=6. These earliest SMBHs may grow by the combination of radiation-pressure-limited accretion and mergers of stellar-mass seed BHs, left behind by the first generation of metal-free stars, or may be formed by more rapid direct collapse of gas in rare special environments where dense gas can accumulate without first fragmenting into stars. This chapter offers a review of these two competing scenarios, as well as some more exotic alternative ideas. It also briefly discusses how the different models may be distinguished in the future by observations with JWST, (e)LISA and other instruments.Comment: 47 pages with 306 references; this review is a chapter in "The First Galaxies - Theoretical Predictions and Observational Clues", Springer Astrophysics and Space Science Library, Eds. T. Wiklind, V. Bromm & B. Mobasher, in pres

Identifying the domains of context important to implementation science: a study protocol

Background There is growing recognition that “context” can and does modify the effects of implementation interventions aimed at increasing healthcare professionals’ use of research evidence in clinical practice. However, conceptual clarity about what exactly comprises “context” is lacking. The purpose of this research program is to develop, refine, and validate a framework that identifies the key domains of context (and their features) that can facilitate or hinder (1) healthcare professionals’ use of evidence in clinical practice and (2) the effectiveness of implementation interventions. Methods/design A multi-phased investigation of context using mixed methods will be conducted. The first phase is a concept analysis of context using the Walker and Avant method to distinguish between the defining and irrelevant attributes of context. This phase will result in a preliminary framework for context that identifies its important domains and their features according to the published literature. The second phase is a secondary analysis of qualitative data from 13 studies of interviews with 312 healthcare professionals on the perceived barriers and enablers to their application of research evidence in clinical practice. These data will be analyzed inductively using constant comparative analysis. For the third phase, we will conduct semi-structured interviews with key health system stakeholders and change agents to elicit their knowledge and beliefs about the contextual features that influence the effectiveness of implementation interventions and healthcare professionals’ use of evidence in clinical practice. Results from all three phases will be synthesized using a triangulation protocol to refine the context framework drawn from the concept analysis. The framework will then be assessed for content validity using an iterative Delphi approach with international experts (researchers and health system stakeholders/change agents). Discussion This research program will result in a framework that identifies the domains of context and their features that can facilitate or hinder: (1) healthcare professionals’ use of evidence in clinical practice and (2) the effectiveness of implementation interventions. The framework will increase the conceptual clarity of the term “context” for advancing implementation science, improving healthcare professionals’ use of evidence in clinical practice, and providing greater understanding of what interventions are likely to be effective in which contexts

Evaluation of Microorganisms Cultured from Injured and Repressed Tissue Regeneration Sites in Endangered Giant Aquatic Ozark Hellbender Salamanders

Investigation into the causes underlying the rapid, global amphibian decline provides critical insight into the effects of changing ecosystems. Hypothesized and confirmed links between amphibian declines, disease, and environmental changes are increasingly represented in published literature. However, there are few long-term amphibian studies that include data on population size, abnormality/injury rates, disease, and habitat variables to adequately assess changes through time. We cultured and identified microorganisms isolated from abnormal/injured and repressed tissue regeneration sites of the endangered Ozark Hellbender, Cryptobranchus alleganiensis bishopi, to discover potential causative agents responsible for their significant decline in health and population. This organism and our study site were chosen because the population and habitat of C. a. bishopi have been intensively studied from 1969–2009, and the abnormality/injury rate and apparent lack of regeneration were established. Although many bacterial and fungal isolates recovered were common environmental organisms, several opportunistic pathogens were identified in association with only the injured tissues of C.a. bishopi. Bacterial isolates included Aeromonas hydrophila, a known amphibian pathogen, Granulicetella adiacens, Gordonai terrae, Stenotrophomonas maltophilia, Aerococcus viridans, Streptococcus pneumoniae and a variety of Pseudomonads, including Pseudomonas aeruginosa, P. stutzeri, and P. alcaligenes. Fungal isolates included species in the genera Penicillium, Acremonium, Cladosporium, Curvularia, Fusarium, Streptomycetes, and the Class Hyphomycetes. Many of the opportunistic pathogens identified are known to form biofilms. Lack of isolation of the same organism from all wounds suggests that the etiological agent responsible for the damage to C. a. bishopi may not be a single organism. To our knowledge, this is the first study to profile the external microbial consortia cultured from a Cryptobranchid salamander. The incidence of abnormalities/injury and retarded regeneration in C. a. bishopi may have many contributing factors including disease and habitat degradation. Results from this study may provide insight into other amphibian population declines