Crystallisation From Volatile Deep Eutectic Solvents

A new class of deep eutectic solvents are presented where one component of the system is inherently volatile, enabling a premeditated, auto-destructive capability which leads inexorably to a series of novel crystal structures. These volatile deep eutectic solvents are easily-formed liquids with a greatly depressed melting point and exhibit all of the physical characteristics of classical deep eutectic solvents, with the exception that the hydrogen-bond donor component is volatile when exposed to the atmosphere at room temperature. We demonstrate the effectiveness of this concept through the exquisite control of pharmaceutical polymorphism, among which is a more efficacious form of acetaminophen, which can be formed spontaneously for the first time at room temperature.Comment: 42 pages, 23 figures, 1 Tabl

NICE's Discounting Review: Clear Thinking on Rational Revision Meets Obstacle of Industrial Interests

The National Institute of Health and Care Excellence (NICE) recently published a review of discounting practice and theory as part of a consultation on its current methods guidelines. The review examines the case for revision or retention of current methods. The changes considered include eliminating favourable rates in certain special cases and the reduction of the base-case rate for costs and health effects from 3.5 to 1.5%. The review also notes the potential need to reduce the cost-effectiveness threshold to accommodate a discount rate reduction, explaining that an agreement between the UK government and the pharmaceutical industry proscribes changing NICE's threshold range until the end of 2023. We believe NICE should be commended for a useful overview of the existing literature and relevant issues. We firmly endorse NICE's view that favourable discount rates are not a good way to apply a preference for certain interventions. Similarly, we support the option of reducing the discount rate to 1.5%, which better accords with real government borrowing costs. We suggest further work to clarify the appropriate theoretical basis for the NICE's social discount rate and the sensitivity of the threshold to changes in discounting. The prospects of a necessary discount rate reduction appear to depend on whether a threshold reduction can be achieved within NICE's current range or if the range itself must be revised downwards. NICE has usefully informed the debate around discount rates. Ultimately, the path to a methodologically consistent and evidence-based revision of discounting depends on whether NICE needs to adjust the threshold too and if it is free to do so.Access provided by IREL Consortium c/o Maynooth University The Library Maynooth Universit

Discounting the Recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine

Twenty years ago, the "Panel on Cost-effectiveness in Health and Medicine" published a landmark text setting out appropriate methods for conducting cost-effectiveness analyses of health technologies. In the two decades since, the methods used for economic evaluations have advanced substantially. Recently, a "second panel" (hereafter "the panel") was convened to update the text and its recommendations were published in November 2016. The purpose of this paper is to critique the panel's updated guidance regarding the discounting of costs and health effects. The advances in discounting methodology since the first panel include greater theoretical clarity regarding the specification of discount rates, how these rates vary with the analytical perspective chosen, and whether the healthcare budget is constrained. More specifically, there has been an important resolution of the debate regarding the conditions under which differential discounting of costs and health effects is appropriate. We show that the panel's recommendations are inconsistent with this recent literature. Importantly, the panel's departures from previously published findings do not arise from an alternative interpretation of theory; rather, we demonstrate that this is due to fundamental errors in methodology and logic. The panel also failed to conduct a formal review of relevant empirical evidence. We provide a number of suggestions for how the panel's recommendations could be improved in future.Access provided by IREL Consortium c/o Maynooth University The Library Maynooth Universit

Association Between Public Reporting of Outcomes With Procedural Management and Mortality for Patients With Acute Myocardial Infarction

AbstractBackgroundPublic reporting of procedural outcomes may create disincentives to provide percutaneous coronary intervention (PCI) for critically ill patients.ObjectivesThis study evaluated the association between public reporting with procedural management and outcomes among patients with acute myocardial infarction (AMI).MethodsUsing the Nationwide Inpatient Sample, we identified all patients with a primary diagnosis of AMI in states with public reporting (Massachusetts and New York) and regionally comparable states without public reporting (Connecticut, Maine, Maryland, New Hampshire, Rhode Island, and Vermont) between 2005 and 2011. Procedural management and in-hospital outcomes were stratified by public reporting.ResultsAmong 84,121 patients hospitalized with AMI, 57,629 (69%) underwent treatment in a public reporting state. After multivariate adjustment, percutaneous revascularization was performed less often in public reporting states than in nonreporting states (odds ratio [OR]: 0.81, 95% confidence interval [CI]: 0.67 to 0.96), especially among older patients (OR: 0.75, 95% CI: 0.62 to 0.91), those with Medicare insurance (OR: 0.75, 95% CI: 0.62 to 0.91), and those presenting with ST-segment elevation myocardial infarction (OR: 0.63, 95% CI: 0.56 to 0.71) or concomitant cardiac arrest or cardiogenic shock (OR: 0.58, 95% CI: 0.47 to 0.70). Overall, patients with AMI in public reporting states had higher adjusted in-hospital mortality rates (OR: 1.21, 95% CI: 1.06 to 1.37) than those in nonreporting states. This was observed predominantly in patients who did not receive percutaneous revascularization in public reporting states (adjusted OR: 1.30, 95% CI: 1.13 to 1.50), whereas those undergoing the procedure had lower mortality (OR: 0.71, 95% CI: 0.62 to 0.83).ConclusionsPublic reporting is associated with reduced percutaneous revascularization and increased in-hospital mortality among patients with AMI, particularly among patients not selected for PCI

dtorsin, the Drosophila Ortholog of the Early-Onset Dystonia TOR1A (DYT1), Plays a Novel Role in Dopamine Metabolism

Dystonia represents the third most common movement disorder in humans. At least 15 genetic loci (DYT1-15) have been identified and some of these genes have been cloned. TOR1A (formally DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. However, the function of torsinA has yet to be fully understood. Here, we have generated and characterized a complete loss-of-function mutant for dtorsin, the only Drosophila ortholog of TOR1A. Null mutation of the X-linked dtorsin was semi-lethal with most male flies dying by the pre-pupal stage and the few surviving adults being sterile and slow moving, with reduced cuticle pigmentation and thin, short bristles. Third instar male larvae exhibited locomotion defects that were rescued by feeding dopamine. Moreover, biochemical analysis revealed that the brains of third instar larvae and adults heterozygous for the loss-of-function dtorsin mutation had significantly reduced dopamine levels. The dtorsin mutant showed a very strong genetic interaction with Pu (Punch: GTP cyclohydrolase), the ortholog of the human gene underlying DYT14 dystonia. Biochemical analyses revealed a severe reduction of GTP cyclohydrolase protein and activity, suggesting that dtorsin plays a novel role in dopamine metabolism as a positive-regulator of GTP cyclohydrolase protein. This dtorsin mutant line will be valuable for understanding this relationship and potentially other novel torsin functions that could play a role in human dystonia

Longitudinal Study of Two Irish Dairy Herds: Low Numbers of Shiga Toxin-Producing Escherichia coli O157 and O26 Super-Shedders Identified

peer-reviewedThe authors wish to acknowledge The Department of Agriculture, Food and Fisheries in Ireland for its financial contribution to the study under the Food Initiative Research Measure (FIRM) Grant No. 11/F/051.A 12-month longitudinal study was undertaken on two dairy herds to ascertain the Shiga-toxin producing Escherichia coli (STEC) O157 and O26 shedding status of the animals and its impact (if any) on raw milk. Cattle are a recognized reservoir for these organisms with associated public health and environmental implications. Animals shedding E. coli O157 at >10,000 CFU/g of feces have been deemed super-shedders. There is a gap in the knowledge regarding super-shedding of other STEC serogroups. A cohort of 40 lactating cows from herds previously identified as positive for STEC in a national surveillance project were sampled every second month between August, 2013 and July, 2014. Metadata on any potential super-shedders was documented including, e.g., age of the animal, number of lactations and days in lactation, nutritional condition, somatic cell count and content of protein in milk to assess if any were associated with risk factors for super-shedding. Recto-anal mucosal swabs (RAMS), raw milk, milk filters, and water samples were procured for each herd. The swabs were examined for E. coli O157 and O26 using a quantitative real time PCR method. Counts (CFU swab-1) were obtained from a standard calibration curve that related real-time PCR cycle threshold (Ct) values against the initial concentration of O157 or O26 in the samples. Results from Farm A: 305 animals were analyzed; 15 E. coli O157 (5%) were recovered, 13 were denoted STEC encoding either stx1 and/or stx2 virulence genes and 5 (2%) STEC O26 were recovered. One super-shedder was identified shedding STEC O26 (stx1&2). Farm B: 224 animals were analyzed; eight E. coli O157 (3.5%) were recovered (seven were STEC) and 9 (4%) STEC O26 were recovered. Three super-shedders were identified, one was shedding STEC O157 (stx2) and two STEC O26 (stx2). Three encoded the adhering and effacement gene (eae) and one isolate additionally encoded the haemolysin gene (hlyA). All four super-shedders were only super-shedding once during the 1-year sampling period. The results of this study show, low numbers of super-shedders in the herds examined, with high numbers of low and medium shedding. Although four super-shedding animals were identified, no STEC O157 or O26 were recovered from any of the raw milk, milk filter, or water samples. The authors conclude that this study highlights the need for further surveillance to assess the potential for environmental contamination and food chain security

Challenges of Profile Likelihood Evaluation in Multi-Dimensional SUSY Scans

Statistical inference of the fundamental parameters of supersymmetric theories is a challenging and active endeavor. Several sophisticated algorithms have been employed to this end. While Markov-Chain Monte Carlo (MCMC) and nested sampling techniques are geared towards Bayesian inference, they have also been used to estimate frequentist confidence intervals based on the profile likelihood ratio. We investigate the performance and appropriate configuration of MultiNest, a nested sampling based algorithm, when used for profile likelihood-based analyses both on toy models and on the parameter space of the Constrained MSSM. We find that while the standard configuration is appropriate for an accurate reconstruction of the Bayesian posterior, the profile likelihood is poorly approximated. We identify a more appropriate MultiNest configuration for profile likelihood analyses, which gives an excellent exploration of the profile likelihood (albeit at a larger computational cost), including the identification of the global maximum likelihood value. We conclude that with the appropriate configuration MultiNest is a suitable tool for profile likelihood studies, indicating previous claims to the contrary are not well founded.Comment: 21 pages, 9 figures, 1 table; minor changes following referee report. Matches version accepted by JHE

The future of evapotranspiration : global requirements for ecosystem functioning, carbon and climate feedbacks, agricultural management, and water resources

The fate of the terrestrial biosphere is highly uncertain given recent and projected changes in climate. This is especially acute for impacts associated with changes in drought frequency and intensity on the distribution and timing of water availability. The development of effective adaptation strategies for these emerging threats to food and water security are compromised by limitations in our understanding of how natural and managed ecosystems are responding to changing hydrological and climatological regimes. This information gap is exacerbated by insufficient monitoring capabilities from local to global scales. Here, we describe how evapotranspiration (ET) represents the key variable in linking ecosystem functioning, carbon and climate feedbacks, agricultural management, and water resources, and highlight both the outstanding science and applications questions and the actions, especially from a space-based perspective, necessary to advance them

Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 4 trial

AbstractObjectives. The aim of our study was to determine a superior tbrombolytic regimen from three: anistreplase (APSAC), frontloaded recombinant tissue-type plasminogen activator (rt-PA) or combination thrombolytic therapy.Background. Although thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction, it has not been clear whether more aggressive thrombolyticantithrombotic regimens could improve the outcome achieved with standard regimens.Methods. To address this issue, 382 patients with acute myocardial infection were randomized to receive in a double-blind fashion (along with intravenous heparin and aspirin) APSAC, front-loaded rt-PA or a combination of both agents. The primary end point “unsatisfactory outcome” was a composite clinical end point assessed through hospital discharge.Results. Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) at 60 min after the start of thrombolysis was significantly higher in rt-PA-treated patients (77.8% vs. 59.5% for APSAC-treated patients and 59.3% for combination-treated patients [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.03]). At 90 min, the incidence of both infarct-related artery patency and TIMI grade 3 flow was significantly higher in rt-PA-treated patients (60.2% had TIMI grade 3 flow vs. 42.9% and 44.8% of APSAC- and combination-treated patients, respectively [rt-PA vs. APSAC, p < 0.01; rt-PA vs. combination, p = 0.02]). The incidence of unsatisfactory outcome was 41.3% for rt-PA compared with 49% for APSAC and 53.6% for the combination (rt-PA vs. APSAC, p = 0.19; rt-PA vs. combination, p = 0.06). The mortality rate at 6 weeks was lowest in the rt-PA-treated patients (2.2% vs. 8.8% for APSAC and 7.2% for combination thrombolytic therapy [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.06]).Conclusions. Front-loaded rt-PA achieved significantly higher rates of early reperfusion and was associated with trends toward better overall clinical benefit and survival than those achieved with a standard thrombolytic agent or combination thrombolytic therapy. These findings support the concept that more rapid reperfusion of the infarct-related artery is associated with improved clinical outcome

Wearable Technology: A Wellbeing Option for Serving Police Officers and Staff? A Comparison of Results of a Pilot Study with Firearms Officers and a Group of Mixed Officers and Staff

The high-stress nature of policing contributes to deterioration of officer health and wellbeing as well as high levels of absenteeism and attrition. Wearable technology (WT) has been identified as a potential tool that can help in improving officer health and wellbeing. This pilot study aimed to give initial insight into acceptability and engagement with WT amongst officers. The study also aimed to uncover any notable areas for exploration in future research within the domain of officer health and wellbeing. Two groups were observed in firearms officers and a mixed group of officers. Participants wore the WT for an extended period, completed a variety of health and wellbeing questionnaires and discussed their experience in focus groups. Firearms officers and mixed group officers displayed similar sleep efficiency, but firearms officers have worse sleep consistency and sleep performance. Firearms officers appear to have higher HRV and slightly lower resting heart rate. Both groups display reasonable acceptance for use of WT speaking favorably during the focus groups of how monitoring the data had improved their quality of life in terms of their understanding of sleep, wellbeing and how they had consequently completed lifestyle modification. WT offers some promise in managing officer health and wellbeing; studies with larger sample sizes are needed to confirm this