Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Background The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. Methods In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. Results A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. Conclusions In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .)

Ticks in the wrong boxes: assessing error in blanket-drag studies due to occasional sampling

BACKGROUND The risk posed by ticks as vectors of disease is typically assessed by blanket-drag sampling of host-seeking individuals. Comparisons of peak abundance between plots - either in order to establish their relative risk or to identify environmental correlates - are often carried out by sampling on one or two occasions during the period of assumed peak tick activity. METHODS This paper simulates this practice by 're-sampling' from model datasets derived from an empirical field study. Re-sample dates for each plot are guided by either the previous year's peak at the plot, or the previous year's peak at a similar, nearby plot. Results from single, double and three-weekly sampling regimes are compared. RESULTS Sampling on single dates within a two-month window of assumed peak activity has the potential to introduce profound errors; sampling on two dates (double sampling) offers greater precision, but three-weekly sampling is the least biased. CONCLUSIONS The common practice of sampling for the abundance of host-seeking ticks on single dates in each plot-year should be strenuously avoided; it is recommended that field acarologists employ regular sampling throughout the year at intervals no greater than three weeks, for a variety of epidemiological studies

The Value of Routinely Collected Data in Evaluating Home Assessment and Modification Interventions to Prevent Falls in Older People: Systematic Literature Review

Background: Falls in older people commonly occur at home. Home assessment and modification (HAM) interventions can be effective in reducing falls; however, there are some concerns over the validity of evaluation findings. Routinely collected data could improve the quality of HAM evaluations and strengthen their evidence base. Objective: The aim of this study is to conduct a systematic review of the evidence of the use of routinely collected data in the evaluations of HAM interventions. Methods: We searched the following databases from inception until January 31, 2020: PubMed, Ovid, CINAHL, OpenGrey, CENTRAL, LILACS, and Web of Knowledge. Eligible studies were those evaluating HAMs designed to reduce falls involving participants aged 60 years or more. We included study protocols and full reports. Bias was assessed using the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool. Results: A total of 7 eligible studies were identified in 8 papers. Government organizations provided the majority of data across studies, with health care providers and third-sector organizations also providing data. Studies used a range of demographic, clinical and health, and administrative data. The purpose of using routinely collected data spanned recruiting and creating a sample, stratification, generating independent variables or covariates, and measuring key study-related outcomes. Nonhome-based modification interventions (eg, in nursing homes) using routinely collected data were not included in this study. We included two protocols, which meant that the results of those studies were not available. MeSH headings were excluded from the PubMed search because of a reduction in specificity. This means that some studies that met the inclusion criteria may not have been identified. Conclusions: Routine data can be used successfully in many aspects of HAM evaluations and can reduce biases and improve other important design considerations. However, the use of these data in these studies is currently not widespread. There are a number of governance barriers to be overcome to allow these types of linkage and to ensure that the use of routinely collected data in evaluations of HAM interventions is exploited to its full potential

Relative Roles of Grey Squirrels, Supplementary Feeding, and Habitat in Shaping Urban Bird Assemblages

Non-native species are frequently considered to influence urban assemblages. The grey squirrel Sciurus carolinensis is one such species that is widespread in the UK and is starting to spread across Europe; it predates birds’ nests and can compete with birds for supplementary food. Using distance sampling across the urbanisation intensity gradient in Sheffield (UK) we test whether urban grey squirrels influence avian species richness and density through nest predation and competition for supplementary food sources. We also assess how urban bird assemblages respond to supplementary feeding. We find that grey squirrels slightly reduced the abundance of breeding bird species most sensitive to squirrel nest predation by reducing the beneficial impact of woodland cover. There was no evidence that grey squirrel presence altered relationships between supplementary feeding and avian assemblage structure. This may be because, somewhat surprisingly, supplementary feeding was not associated with the richness or density of wintering bird assemblages. These associations were positive during the summer, supporting advocacy to feed birds during the breeding season and not just winter, but explanatory capacity was limited. The amount of green space and its quality, assessed as canopy cover, had a stronger influence on avian species richness and population size than the presence of grey squirrels and supplementary feeding stations. Urban bird populations are thus more likely to benefit from investment in improving the availability of high quality habitats than controlling squirrel populations or increased investment in supplementary feeding

Should Research Ethics Encourage the Production of Cost-Effective Interventions?

This project considers whether and how research ethics can contribute to the provision of cost-effective medical interventions. Clinical research ethics represents an underexplored context for the promotion of cost-effectiveness. In particular, although scholars have recently argued that research on less-expensive, less-effective interventions can be ethical, there has been little or no discussion of whether ethical considerations justify curtailing research on more expensive, more effective interventions. Yet considering cost-effectiveness at the research stage can help ensure that scarce resources such as tissue samples or limited subject popula- tions are employed where they do the most good; can support parallel efforts by providers and insurers to promote cost-effectiveness; and can ensure that research has social value and benefits subjects. I discuss and rebut potential objections to the consideration of cost-effectiveness in research, including the difficulty of predicting effectiveness and cost at the research stage, concerns about limitations in cost-effectiveness analysis, and worries about overly limiting researchers’ freedom. I then consider the advantages and disadvantages of having certain participants in the research enterprise, including IRBs, advisory committees, sponsors, investigators, and subjects, consider cost-effectiveness. The project concludes by qualifiedly endorsing the consideration of cost-effectiveness at the research stage. While incorporating cost-effectiveness considerations into the ethical evaluation of human subjects research will not on its own ensure that the health care system realizes cost-effectiveness goals, doing so nonetheless represents an important part of a broader effort to control rising medical costs

The hr1 and Fusion Peptide Regions of the Subgroup B Avian Sarcoma and Leukosis Virus Envelope Glycoprotein Influence Low pH-Dependent Membrane Fusion

The avian sarcoma and leukosis virus (ASLV) envelope glycoprotein (Env) is activated to trigger fusion by a two-step mechanism involving receptor-priming and low pH fusion activation. In order to identify regions of ASLV Env that can regulate this process, a genetic selection method was used to identify subgroup B (ASLV-B) virus-infected cells resistant to low pH-triggered fusion when incubated with cells expressing the cognate TVB receptor. The subgroup B viral Env (envB) genes were then isolated from these cells and characterized by DNA sequencing. This led to identification of two frequent EnvB alterations which allowed TVB receptor-binding but altered the pH-threshold of membrane fusion activation: a 13 amino acid deletion in the host range 1 (hr1) region of the surface (SU) EnvB subunit, and the A32V amino acid change within the fusion peptide of the transmembrane (TM) EnvB subunit. These data indicate that these two regions of EnvB can influence the pH threshold of fusion activation

The effect of temperature on growth and competition between Sphagnum species

Peat bogs play a large role in the global sequestration of C, and are often dominated by different Sphagnum species. Therefore, it is crucial to understand how Sphagnum vegetation in peat bogs will respond to global warming. We performed a greenhouse experiment to study the effect of four temperature treatments (11.2, 14.7, 18.0 and 21.4°C) on the growth of four Sphagnum species: S. fuscum and S. balticum from a site in northern Sweden and S. magellanicum and S. cuspidatum from a site in southern Sweden. In addition, three combinations of these species were made to study the effect of temperature on competition. We found that all species increased their height increment and biomass production with an increase in temperature, while bulk densities were lower at higher temperatures. The hollow species S. cuspidatum was the least responsive species, whereas the hummock species S. fuscum increased biomass production 13-fold from the lowest to the highest temperature treatment in monocultures. Nutrient concentrations were higher at higher temperatures, especially N concentrations of S. fuscum and S. balticum increased compared to field values. Competition between S. cuspidatum and S. magellanicum was not influenced by temperature. The mixtures of S. balticum with S. fuscum and S. balticum with S. magellanicum showed that S. balticum was the stronger competitor, but it lost competitive advantage in the highest temperature treatment. These findings suggest that species abundances will shift in response to global warming, particularly at northern sites where hollow species will lose competitive strength relative to hummock species and southern species

A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Rofecoxib for dysmenorrhoea: meta-analysis using individual patient data

BACKGROUND: Individual patient meta-analysis to determine the analgesic efficacy and adverse effects of single-dose rofecoxib in primary dysmenorrhoea. METHODS: Individual patient information was available from three randomised, double blind, placebo and active controlled trials of rofecoxib. Data were combined through meta-analysis. Number-needed-to-treat (NNT) for at least 50% pain relief and the proportion of patients who had taken rescue medication over 12 hours were calculated. Information was collected on adverse effects. RESULTS: For single-dose rofecoxib 50 mg compared with placebo, the NNTs (with 95% CI) for at least 50% pain relief were 3.2 (2.4 to 4.5) at six, 3.1 (2.4 to 9.0) at eight, and 3.7 (2.8 to 5.6) at 12 hours. For naproxen sodium 550 mg they were 3.1 (2.4 to 4.4) at six, 3.0 (2.3 to 4.2) at eight, and 3.8 (2.7 to 6.1) at 12 hours. The proportion of patients who needed rescue medication within 12 hours was 27% with rofecoxib 50 mg, 29% with naproxen sodium 550 mg, and 50% with placebo. In the single-dose trial, the proportion of patients reporting any adverse effect was 8% (4/49) with rofecoxib 50 mg, 12% (6/49) with ibuprofen 400 mg, and 6% (3/49) with placebo. In the other two multiple dose trials, the proportion of patients reporting any adverse effect was 23% (42/179) with rofecoxib 50 mg, 24% (45/181) with naproxen sodium 550 mg, and 18% (33/178) with placebo. CONCLUSIONS: Single dose rofecoxib 50 mg provided similar pain relief to naproxen sodium 550 mg over 12 hours. The duration of analgesia with rofecoxib 50 mg was similar to that of naproxen sodium 550 mg. Adverse effects were uncommon suggesting safety in short-term use of rofecoxib and naproxen sodium. Future research should include restriction on daily life and absence from work or school as outcomes