Intentional and unintentional non-adherence in community dwelling people with type 2 diabetes: the effect of varying numbers of medicines

People with type 2 diabetes are often prescribed multiple medicines which can be difficult to manage. Nonadherence to medicines can be intentional (e.g. active decision) or unintentional (e.g. forgetting). The objective of this study was to measure intentional and unintentional non-adherence to differing numbers of medicines prescribed in type 2 diabetes. A cross sectional survey using the Morisky medication adherence scale (with intentional and unintentional non-adherence subscales) was completed by 480 people prescribed oral antidiabetic drugs (OADs), antihypertensive agents and statins. A within-subject analysis of variance (ANOVA) showed that intentional non-adherence did not vary between OADs, anti-hypertensives and statins. Intentional non-adherence to statins significantly increased when the number of medicines prescribed was included as a between-subjects variable (p<0.05). Another within-subject ANOVA on unintentional non-adherence found a significant difference between OADs, anti-hypertensives and statins; unintentional non-adherence to OADs was significantly higher (p<0.05). When the number of medicines was added as a between-subject variable unintentional non-adherence was associated with higher numbers of medicines. This study shows the difference between intentional and unintentional non-adherence behaviours, and the effect that varying numbers of medicines can have on these behaviours

Large sulfur isotope fractionations in Martian sediments at Gale crater

Variability in the sulfur isotopic composition in sediments can reflect atmospheric, geologic and biological processes. Evidence for ancient fluvio-lacustrine environments at Gale crater on Mars and a lack of efficient crustal recycling mechanisms on the planet suggests a surface environment that was once warm enough to allow the presence of liquid water, at least for discrete periods of time, and implies a greenhouse effect that may have been influenced by sulfur-bearing volcanic gases. Here we report in situ analyses of the sulfur isotopic compositions of SO2 volatilized from ten sediment samples acquired by NASA’s Curiosity rover along a 13 km traverse of Gale crater. We find large variations in sulfur isotopic composition that exceed those measured for Martian meteorites and show both depletion and enrichment in 34S. Measured values of δ34S range from −47 ± 14‰ to 28 ± 7‰, similar to the range typical of terrestrial environments. Although limited geochronological constraints on the stratigraphy traversed by Curiosity are available, we propose that the observed sulfur isotopic signatures at Gale crater can be explained by equilibrium fractionation between sulfate and sulfide in an impact-driven hydrothermal system and atmospheric processing of sulfur-bearing gases during transient warm periods

Proteomics and phylogenetic analysis of the cathepsin L protease family of the helminth pathogen Fasciola hepatica: Expansion of a repertoire of virulence-associated factors

Cathepsin L proteases secreted by the helminth pathogen Fasciola hepatica have functions in parasite virulence including tissue invasion and suppression of host immune responses. Using proteomics methods alongside phylogenetic studies we characterized the profile of cathepsin L proteases secreted by adult F. hepatica and hence identified those involved in host-pathogen interaction. Phylogenetic analyses showed that the Fasciola cathepsin L gene family expanded by a series of gene duplications followed by divergence that gave rise to three clades associated with mature adult worms (Clades 1, 2, and 5) and two clades specific to infective juvenile stages (Clades 3 and 4). Consistent with these observations our proteomics studies identified representatives from Clades 1, 2, and 5 but not from Clades 3 and 4 in adult F. hepatica secretory products. Clades 1 and 2 account for 67.39 and 27.63% of total secreted cathepsin Ls, respectively, suggesting that their expansion was positively driven and that these proteases are most critical for parasite survival and adaptation. Sequence comparison studies revealed that the expansion of cathepsin Ls by gene duplication was followed by residue changes in the S2 pocket of the active site. Our biochemical studies showed that these changes result in alterations in substrate binding and suggested that the divergence of the cathepsin L family produced a repertoire of enzymes with overlapping and complementary substrate specificities that could cleave host macromolecules more efficiently. Although the cathepsin Ls are produced as zymogens containing a prosegment and mature domain, all secreted enzymes identified by MS were processed to mature active enzymes. The prosegment region was highly conserved between the clades except at the boundary of prosegment and mature enzyme. Despite the lack of conservation at this section, sites for exogenous cleavage by asparaginyl endopeptidases and a Leu-Ser ↓ His motif for autocatalytic cleavage by cathepsin Ls were preserved. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc

The potassic sedimentary rocks in Gale Crater, Mars, as seen by ChemCam on board Curiosity

The Mars Science Laboratory rover Curiosity encountered potassium-rich clastic sedimentary rocks at two sites in Gale Crater, the waypoints Cooperstown and Kimberley. These rocks include several distinct meters thick sedimentary outcrops ranging from fine sandstone to conglomerate, interpreted to record an ancient fluvial or fluvio-deltaic depositional system. From ChemCam Laser-Induced Breakdown Spectroscopy (LIBS) chemical analyses, this suite of sedimentary rocks has an overall mean K2O abundance that is more than 5 times higher than that of the average Martian crust. The combined analysis of ChemCam data with stratigraphic and geographic locations reveals that the mean K2O abundance increases upward through the stratigraphic section. Chemical analyses across each unit can be represented as mixtures of several distinct chemical components, i.e., mineral phases, including K-bearing minerals, mafic silicates, Fe-oxides, and Fe-hydroxide/oxyhydroxides. Possible K-bearing minerals include alkali feldspar (including anorthoclase and sanidine) and K-bearing phyllosilicate such as illite. Mixtures of different source rocks, including a potassium-rich rock located on the rim and walls of Gale Crater, are the likely origin of observed chemical variations within each unit. Physical sorting may have also played a role in the enrichment in K in the Kimberley formation. The occurrence of these potassic sedimentary rocks provides additional evidence for the chemical diversity of the crust exposed at Gale Crater

Structural and functional relationships in the virulence-associated cathepsin L proteases of the parasitic liver fluke, Fasciola hepatica

The helminth parasite Fasciola hepatica secretes cysteine proteases to facilitate tissue invasion, migration, and development within the mammalian host. The major proteases cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) were recombinantly produced and biochemically characterized. By using site-directed mutagenesis, we show that residues at position 67 and 205, which lie within the S2 pocket of the active site, are critical in determining the substrate and inhibitor specificity. FheCL1 exhibits a broader specificity and a higher substrate turnover rate compared with FheCL2. However, FheCL2 can efficiently cleave substrates with a Pro in the P2 position and degrade collagen within the triple helices at physiological pH, an activity that among cysteine proteases has only been reported forhuman cathepsin K. The 1.4-Å three-dimensional structure of the FheCL1 was determined by x-ray crystallography, and the three-dimensional structure of FheCL2 was constructed via homology-based modeling. Analysis and comparison of these structures and our biochemical data with those of human cathepsins L and Kprovided an interpretation of the substrate-recognition mechanisms of these major parasite proteases. Furthermore, our studies suggest that a configuration involving residue 67 and the "gatekeeper" residues 157 and 158 situated at the entrance of the active site pocket create a topology that endows FheCL2 with its unusual collagenolytic activity. The emergence of a specialized collagenolytic function in Fasciola likely contributes to the success of this tissue-invasive parasite. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc

Comparing orbiter and rover image-based mapping of an ancient sedimentary environment, Aeolis Palus, Gale crater, Mars

This study provides the first systematic comparison of orbital facies maps with detailed ground-based geology observations from the Mars Science Laboratory (MSL) Curiosity rover to examine the validity of geologic interpretations derived from orbital image data. Orbital facies maps were constructed for the Darwin, Cooperstown, and Kimberley waypoints visited by the Curiosity rover using High Resolution Imaging Science Experiment (HiRISE) images. These maps, which represent the most detailed orbital analysis of these areas to date, were compared with rover image-based geologic maps and stratigraphic columns derived from Curiosity's Mast Camera (Mastcam) and Mars Hand Lens Imager (MAHLI). Results show that bedrock outcrops can generally be distinguished from unconsolidated surficial deposits in high-resolution orbital images and that orbital facies mapping can be used to recognize geologic contacts between well-exposed bedrock units. However, process-based interpretations derived from orbital image mapping are difficult to infer without known regional context or observable paleogeomorphic indicators, and layer-cake models of stratigraphy derived from orbital maps oversimplify depositional relationships as revealed from a rover perspective. This study also shows that fine-scale orbital image-based mapping of current and future Mars landing sites is essential for optimizing the efficiency and science return of rover surface operations

The Importance of pH in Regulating the Function of the Fasciola hepatica Cathepsin L1 Cysteine Protease

The helminth parasite Fasciola hepatica secretes cathepsin L cysteine proteases to invade its host, migrate through tissues and digest haemoglobin, its main source of amino acids. Here we investigated the importance of pH in regulating the activity and functions of the major cathepsin L protease FheCL1. The slightly acidic pH of the parasite gut facilitates the auto-catalytic activation of FheCL1 from its inactive proFheCL1 zymogen; this process was ∼40-fold faster at pH 4.5 than at pH 7.0. Active mature FheCL1 is very stable at acidic and neutral conditions (the enzyme retained ∼45% activity when incubated at 37°C and pH 4.5 for 10 days) and displayed a broad pH range for activity peptide substrates and the protein ovalbumin, peaking between pH 5.5 and pH 7.0. This pH profile likely reflects the need for FheCL1 to function both in the parasite gut and in the host tissues. FheCL1, however, could not cleave its natural substrate Hb in the pH range pH 5.5 and pH 7.0; digestion occurred only at pH≤4.5, which coincided with pH-induced dissociation of the Hb tetramer. Our studies indicate that the acidic pH of the parasite relaxes the Hb structure, making it susceptible to proteolysis by FheCL1. This process is enhanced by glutathione (GSH), the main reducing agent contained in red blood cells. Using mass spectrometry, we show that FheCL1 can degrade Hb to small peptides, predominantly of 4–14 residues, but cannot release free amino acids. Therefore, we suggest that Hb degradation is not completed in the gut lumen but that the resulting peptides are absorbed by the gut epithelial cells for further processing by intracellular di- and amino-peptidases to free amino acids that are distributed through the parasite tissue for protein anabolism

Accelerating Policy Decisions to Adopt Haemophilus influenzae Type b Vaccine: A Global, Multivariable Analysis

Jessica Shearer and colleagues analyze data from 147 countries to identify factors that influence the time taken to introduce routine vaccination against Haemophilus influenzae type b (Hib)

Evidence for plunging river plume deposits in the Pahrump Hills member of the Murray formation, Gale crater, Mars

Recent robotic missions to Mars have offered new insights into the extent, diversity and habitability of the Martian sedimentary rock record. Since the Curiosity rover landed in Gale crater in August 2012, the Mars Science Laboratory Science Team has explored the origins and habitability of ancient fluvial, deltaic, lacustrine and aeolian deposits preserved within the crater. This study describes the sedimentology of a ca 13 m thick succession named the Pahrump Hills member of the Murray formation, the first thick fine‐grained deposit discovered in situ on Mars. This work evaluates the depositional processes responsible for its formation and reconstructs its palaeoenvironmental setting. The Pahrump Hills succession can be sub‐divided into four distinct sedimentary facies: (i) thinly laminated mudstone; (ii) low‐angle cross‐stratified mudstone; (iii) cross‐stratified sandstone; and (iv) thickly laminated mudstone–sandstone. The very fine grain size of the mudstone facies and abundant millimetre‐scale and sub‐millimetre‐scale laminations exhibiting quasi‐uniform thickness throughout the Pahrump Hills succession are most consistent with lacustrine deposition. Low‐angle geometric discordances in the mudstone facies are interpreted as ‘scour and drape’ structures and suggest the action of currents, such as those associated with hyperpycnal river‐generated plumes plunging into a lake. Observation of an overall upward coarsening in grain size and thickening of laminae throughout the Pahrump Hills succession is consistent with deposition from basinward progradation of a fluvial‐deltaic system derived from the northern crater rim into the Gale crater lake. Palaeohydraulic modelling constrains the salinity of the ancient lake in Gale crater: assuming river sediment concentrations typical of floods on Earth, plunging river plumes and sedimentary structures like those observed at Pahrump Hills would have required lake densities near freshwater to form. The depositional model for the Pahrump Hills member presented here implies the presence of an ancient sustained, habitable freshwater lake in Gale crater for at least ca 103 to 107 Earth years

A systematic review of patient and health system characteristics associated with late referral in chronic kidney disease

<p>Abstract</p> <p>Background</p> <p>To identify patient and health system characteristics associated with late referral of patients with chronic kidney disease to nephrologists.</p> <p>Methods</p> <p>MEDLINE, CENTRAL, and CINAHL were searched using the appropriate MESH terms in March 2007. Two reviewers individually and in duplicate reviewed the abstracts of 256 articles and selected 18 observational studies for inclusion. The reasons for late referral were categorized into patient or health system characteristics. Data extraction and content appraisal were done using a prespecified protocol.</p> <p>Results</p> <p>Older age, the existence of multiple comorbidities, race other than Caucasian, lack of insurance, lower socioeconomic status and educational levels were patient characteristics associated with late referral of patients with chronic kidney disease. Lack of referring physician knowledge about the appropriate timing of referral, absence of communication between referring physicians and nephrologists, and dialysis care delivered at tertiary medical centers were health system characteristics associated with late referral of patients with chronic kidney disease. Most studies identified multiple factors associated with late referral, although the relative importance and the combined effect of these factors were not systematically evaluated.</p> <p>Conclusion</p> <p>A combination of patient and health system characteristics is associated with late referral of patients with chronic kidney disease. Overall, being older, belonging to a minority group, being less educated, being uninsured, suffering from multiple comorbidities, and the lack of communication between primary care physicians and nephrologists contribute to late referral of patients with chronic kidney disease. Both primary care physicians and nephrologists need to engage in multisectoral collaborative efforts that ensure patient education and enhance physician awareness to improve the care of patients with chronic kidney disease.</p