Legal and professional implications of shared care: a case study in oral anticoagulation stroke prevention therapy.

Policy initiatives and technological advances enable the use of integrated shared care models of healthcare delivery whereby the focus of care is moved from the hospital to the community, and also of models where patients take increasing responsibility for monitoring and treatment. Such shifts may or may be perceived to change professional roles and responsibilities with implications to the delivery of a professionally and legally acceptable standard of care. We focus on oral anticoagulation and stroke prevention therapy to examine some possible professional and legal implications of the increasing use of shared care

Basal melting of Ross Ice Shelf from solar heat absorption in an ice-front polynya

Ice-ocean interactions at the base of Antarctic ice shelves are rarely observed, yet have a profound influence on ice sheet evolution and stability. Ice sheet models are highly sensitive to assumed ice shelf basal melt rates; however, there are few direct observations of basal melting or the oceanographic processes that drive this, and consequently our understanding of these interactions remains limited. Here we use new in-situ observations from the Ross Ice Shelf to examine the oceanographic processes that drive basal ablation of the world’s largest ice shelf. We show that basal melt rates beneath a thin and structurally important part of the shelf are an order of magnitude higher than the shelf-wide average. This melting is strongly influenced by a seasonal inflow of solar-heated surface water from the adjacent Ross Sea Polynya that downwells into the ice shelf cavity, nearly tripling basal melt rates during summer. Melting driven by this frequently overlooked process is expected to increase with predicted surface warming. We infer that solar heat absorbed in ice front polynyas can make an important contribution to the present-day mass balance of ice shelves, and potentially impact their future stability.Rutherford Foundation and Antarctica New Zealan

Impacts of natural and human drivers on the multi-decadal morphological evolution of tidally-influenced deltas

The world's deltas are at risk of being drowned due to rising relative sea levels as a result of climate change, decreasing supplies of fluvial sediment, and human responses to these changes. This paper analyses how delta morphology evolves over multi-decadal timescales under environmental change using a process-based model. Model simulations over 10^2 years are used to explore the influence of three key classes of environmental change, both individually and in combination: (i) varying combinations of fluvial water and sediment discharges; (ii) varying rates of relative sea-level rise; and (iii) selected human interventions within the delta, comprising polder-dykes and cross-dams. The results indicate that tidal asymmetry and rate of sediment supply together affect residual flows and delta morphodynamics (indicated by sub-aerial delta area, rates of progradation and aggradation). When individual drivers of change act in combination, delta building processes such as the distribution of sediment flux, aggradation, and progradation are disrupted by the presence of isolated polder-dykes or cross-dams. This suggests that such interventions, unless undertaken at a very large scale, can lead to unsustainable delta building processes. Our findings can inform management choices in real-world tidally-influenced deltas, while the methodology can provide insights into other dynamic morphological systems

Guanidine-Catalyzed Reductive Amination of Carbon Dioxide with Silanes: Switching between Pathways and Suppressing Catalyst Deactivation

A mechanistic investigation into the guanidine-catalyzed reductive amination of CO₂, using a combination of ¹H, ²⁹Si NMR, FT-IR, MS, and GC profiling, is reported. Inexpensive and readily available N,N,N′,N′-tetramethylguanidine (TMG) was found to be an equally effective catalyst compared to more elaborate cyclic guanidines. Different catalytic pathways to formamide 2, aminal 4, and N-methylamine 3 were identified. A pathway to formamide product 2 dominates at 23 °C. Increasing the reaction temperature to 60 °C enables a competitive, higher-energy pathway to 4 and 3, which requires direct reduction of CO₂ with PhSiH₃ to formoxysilane E. Reduction of aminal 4, in the presence of CO₂ and the catalyst, led to formation of a 1:1 ratio of 2 and 3. The catalyst itself can be formylated under the reaction conditions, resulting in its deactivation. Thus, alkylated TMGs were found to be more stable and more active catalysts than TMG, leading to a successful organocatalyzed reductive functionalization of CO₂ with silane at 0.1 mol % catalyst loading (TON = 805 and TOF = 33.5 h‾¹)

Metabolomics dataset of PPAR-pan treated rat liver

This article contains mass spectrometry (MS) data investigating small molecule changes as an effect of a triple peroxisome proliferator-activated receptor (PPAR-pan) agonist GW625019 in the liver as described in the manuscript (Ament et al., 2016) [1]. Samples were measured using gas chromatography-mass spectrometry (GC–MS) for total fatty acid content, and liquid chromatography-mass spectrometry (LC–MS) to measure intact lipids, carnitines and selected aqueous metabolites and eicosanoids. Data files comprise of Excel (Microsoft, WA, USA) spreadsheets of identified metabolites and their area ratio values for total fatty acids, carnitines, aqueous metabolites, and eicosanoids where the intensity of the analytes were normalised to the intensity of the internal standard. In the case of open profiling intact lipid data, the Excel file contains area ratio values of retention time and mass to charge ratio pairs; again, the area ratio values were calculated by normalising to the intensity of the internal standard. It should be noted that several metabolic changes are potentially indirect (secondary, tertiary and ensuing changes)

PubChem3D: Diversity of shape

<p>Abstract</p> <p>Background</p> <p>The shape diversity of 16.4 million biologically relevant molecules from the PubChem Compound database and their 1.46 billion diverse conformers was explored as a function of molecular volume.</p> <p>Results</p> <p>The diversity of shape space was investigated by determining the shape similarity threshold to achieve a maximum on the count of reference shapes per unit of conformer volume. The rate of growth in shape space, as represented by a decreasing shape similarity threshold, was found to be remarkably smooth as a function of volume. There was no apparent correlation between the count of conformers per unit volume and their diversity, meaning that a single reference shape can describe the shape space of many chemical structures. The ability of a volume to describe the shape space of lesser volumes was also examined. It was shown that a given volume was able to describe 40-70% of the shape diversity of lesser volumes, for the majority of the volume range considered in this study.</p> <p>Conclusion</p> <p>The relative growth of shape diversity as a function of volume and shape similarity is surprisingly uniform. Given the distribution of chemicals in PubChem versus what is theoretically synthetically possible, the results from this analysis should be considered a conservative estimate to the true diversity of shape space.</p

Community impacts of anthropogenic disturbance: natural enemies exploit multiple routes in pursuit of invading herbivore hosts.

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Biological invasions provide a window on the process of community assembly. In particular, tracking natural enemy recruitment to invading hosts can reveal the relative roles of co-evolution (including local adaptation) and ecological sorting. We use molecular data to examine colonisation of northern Europe by the parasitoid Megastigmus stigmatizans following invasions of its herbivorous oak gallwasp hosts from the Balkans. Local host adaptation predicts that invading gallwasp populations will have been tracked primarily by sympatric Balkan populations of M. stigmatizans (Host Pursuit Hypothesis). Alternatively, ecological sorting allows parasitoid recruitment from geographically distinct populations with no recent experience of the invading hosts (Host Shift Hypothesis). Finally, we test for long-term persistence of parasitoids introduced via human trade of their hosts' galls (Introduction Hypothesis). RESULTS: Polymorphism diagnostic of different southern refugial regions was present in both mitochondrial and nuclear microsatellite markers, allowing us to identify the origins of northern European invaded range M. stigmatizans populations. As with their hosts, some invaded range populations showed genetic variation diagnostic of Balkan sources, supporting the Host Pursuit Hypothesis. In contrast, other invading populations had an Iberian origin, unlike their hosts in northern Europe, supporting the Host Shift Hypothesis. Finally, both British and Italian M. stigmatizans populations show signatures compatible with the Introduction Hypothesis from eastern Mediterranean sources. CONCLUSIONS: These data reveal the continental scale of multi-trophic impacts of anthropogenic disturbance and highlight the fact that herbivores and their natural enemies may face very different constraints on range expansion. The ability of natural enemies to exploit ecologically-similar hosts with which they have had no historical association supports a major role for ecological sorting processes in the recent assembly of these communities. The multitude of origins of invading natural enemy populations in this study emphasises the diversity of mechanisms requiring consideration when predicting consequences of other biological invasions or biological control introductions.Funding was provided by NERC grant NE/B504406/1 to GNS and KS and NE/E014453/1 to GNS and JAN

Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study

Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001–012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16–74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi

Mitochondria and the regulation of free radical damage in the eye

Neuronal cell death can be determined by the overall level of reactive oxygen species (ROS) resulting from the combination of extrinsic sources and intrinsic production as a byproduct of oxidative phosphorylation. Key controllers of the intrinsic production of ROS are the mitochondrial uncoupling proteins (UCPs). By allowing a controlled leak of protons across the inner mitochondrial membrane activation of these proteins can decrease ROS and promote cell survival. In both primate models of Parkinson’s disease and mouse models of seizures, increased activity of UCP2 significantly increased neuronal cells survival. In the retina UCP2 is expressed in many neurons and glial cells, but was not detected in rod photoreceptors. Retinal ganglion cell survival following excitotoxic damage was much greater in animals overexpressing UCP2. Traditional Chinese medicines, such as an extract of Cistanche tubulosa, may provide benefit by altering mitochondrial metabolism

What do we know and when do we know it?

Two essential aspects of virtual screening are considered: experimental design and performance metrics. In the design of any retrospective virtual screen, choices have to be made as to the purpose of the exercise. Is the goal to compare methods? Is the interest in a particular type of target or all targets? Are we simulating a ‘real-world’ setting, or teasing out distinguishing features of a method? What are the confidence limits for the results? What should be reported in a publication? In particular, what criteria should be used to decide between different performance metrics? Comparing the field of molecular modeling to other endeavors, such as medical statistics, criminology, or computer hardware evaluation indicates some clear directions. Taken together these suggest the modeling field has a long way to go to provide effective assessment of its approaches, either to itself or to a broader audience, but that there are no technical reasons why progress cannot be made