Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: Data from the Italian AIFA Anti-diabetics Monitoring Registry

AbstractBackground and aimsIn Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry.Methods and resultsFrom February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (≥75 years, n = 6125 cases), body mass index (BMI) (≥35 kg/m2, n = 22,015), and metabolic control (HbA1c ≥ 11% ((96 mmol/mol), n = 3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21–26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27–40% of all discontinuations, after excluding lost to follow-up. HbA1c decreased on average by 0.9–1.0% (9 mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0–1.5% with DPP-4 inhibitors.ConclusionsIn the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials

Using the latest resistance score to predict etravirine (ETV) resistance in naïve and NNRTI-failing patients

Methods A set of 17 mutations (V90I, A98G, L100I, K101E/H/P, V106I, E138A, V179D/F/T, Y181C/I/V, G190A/S, M230L) were found associated with ETV resistance in the Phase III DUET-1 and DUET-2 trials. Recently, a different score was assigned to each mutation (i.e. Y181C/I have the highest score: 3). An overall score of ≤4 was associated with reduced response and a score between 2.5–3.5 with intermediate response (reference). ETV resistance was calculated from a large database of patients undergoing genotypic resistance test

Patient and Regimen Characteristics Associated with Self-Reported Nonadherence to Antiretroviral Therapy

BACKGROUND: Nonadherence to antiretroviral therapy (ARVT) is an important behavioral determinant of the success of ARVT. Nonadherence may lead to virological failure, and increases the risk of development of drug resistance. Understanding the prevalence of nonadherence and associated factors is important to inform secondary HIV prevention efforts. METHODOLOGY/PRINCIPAL FINDINGS: We used data from a cross-sectional interview study of persons with HIV conducted in 18 U.S. states from 2000-2004. We calculated the proportion of nonadherent respondents (took <95% of prescribed doses in the past 48 hours), and the proportion of doses missed. We used multivariate logistic regression to describe factors associated with nonadherence. Nine hundred and fifty-eight (16%) of 5,887 respondents reported nonadherence. Nonadherence was significantly (p<0.05) associated with black race and Hispanic ethnicity; age <40 years; alcohol or crack use in the prior 12 months; being prescribed >or=4 medications; living in a shelter or on the street; and feeling "blue" >or=14 of the past 30 days. We found weaker associations with having both male-male sex and injection drug use risks for HIV acquisition; being prescribed ARVT for >or=21 months; and being prescribed a protease inhibitor (PI)-based regimen not boosted with ritonavir. The median proportion of doses missed was 50%. The most common reasons for missing doses were forgetting and side effects. CONCLUSIONS/SIGNIFICANCE: Self-reported recent nonadherence was high in our study. Our data support increased emphasis on adherence in clinical settings, and additional research on how providers and patients can overcome barriers to adherence

AIC, BIC, Bayesian evidence against the interacting dark energy model

Recent astronomical observations have indicated that the Universe is in the phase of accelerated expansion. While there are many cosmological models which try to explain this phenomenon, we focus on the interacting $\Lambda$CDM model where the interaction between the dark energy and dark matter sectors takes place. This model is compared to its simpler alternative---the $\Lambda$CDM model. To choose between these models the likelihood ratio test was applied as well as the model comparison methods (employing Occam's principle): the Akaike information criterion (AIC), the Bayesian information criterion (BIC) and the Bayesian evidence. Using the current astronomical data: SNIa (Union2.1), $h(z)$, BAO, Alcock--Paczynski test and CMB we evaluated both models. The analyses based on the AIC indicated that there is less support for the interacting $\Lambda$CDM model when compared to the $\Lambda$CDM model, while those based on the BIC indicated that there is the strong evidence against it in favor the $\Lambda$CDM model. Given the weak or almost none support for the interacting $\Lambda$CDM model and bearing in mind Occam's razor we are inclined to reject this model.Comment: LaTeX svjour3, 12 pages, 3 figure

Regulation of Cyclooxygenase-2 Expression by Heat: A Novel Aspect of Heat Shock Factor 1 Function in Human Cells

The heat-shock response, a fundamental defense mechanism against proteotoxic stress, is regulated by a family of heat-shock transcription factors (HSF). In humans HSF1 is considered the central regulator of heat-induced transcriptional responses. The main targets for HSF1 are specific promoter elements (HSE) located upstream of heat-shock genes encoding cytoprotective heat-shock proteins (HSP) with chaperone function. In addition to its cytoprotective function, HSF1 was recently hypothesized to play a more complex role, regulating the expression of non-HSP genes; however, the non-canonical role of HSF1 is still poorly understood. Herein we report that heat-stress promotes the expression of cyclooxygenase-2 (COX-2), a key regulator of inflammation controlling prostanoid and thromboxane synthesis, resulting in the production of high levels of prostaglandin-E2 in human cells. We show that heat-induced COX-2 expression is regulated at the transcriptional level via HSF1-mediated signaling and identify, by in-vitro reporter gene activity assay and deletion-mutant constructs analysis, the COX-2 heat-responsive promoter region and a new distal cis-acting HSE located at position −2495 from the transcription start site. As shown by ChIP analysis, HSF1 is recruited to the COX-2 promoter rapidly after heat treatment; by using shRNA-mediated HSF1 suppression and HSE-deletion from the COX-2 promoter, we demonstrate that HSF1 plays a central role in the transcriptional control of COX-2 by heat. Finally, COX-2 transcription is also induced at febrile temperatures in endothelial cells, suggesting that HSF1-dependent COX-2 expression could contribute to increasing blood prostaglandin levels during fever. The results identify COX-2 as a human non-classical heat-responsive gene, unveiling a new aspect of HSF1 function

Do Stacked Species Distribution Models Reflect Altitudinal Diversity Patterns?

The objective of this study was to evaluate the performance of stacked species distribution models in predicting the alpha and gamma species diversity patterns of two important plant clades along elevation in the Andes. We modelled the distribution of the species in the Anthurium genus (53 species) and the Bromeliaceae family (89 species) using six modelling techniques. We combined all of the predictions for the same species in ensemble models based on two different criteria: the average of the rescaled predictions by all techniques and the average of the best techniques. The rescaled predictions were then reclassified into binary predictions (presence/absence). By stacking either the original predictions or binary predictions for both ensemble procedures, we obtained four different species richness models per taxa. The gamma and alpha diversity per elevation band (500 m) was also computed. To evaluate the prediction abilities for the four predictions of species richness and gamma diversity, the models were compared with the real data along an elevation gradient that was independently compiled by specialists. Finally, we also tested whether our richness models performed better than a null model of altitudinal changes of diversity based on the literature. Stacking of the ensemble prediction of the individual species models generated richness models that proved to be well correlated with the observed alpha diversity richness patterns along elevation and with the gamma diversity derived from the literature. Overall, these models tend to overpredict species richness. The use of the ensemble predictions from the species models built with different techniques seems very promising for modelling of species assemblages. Stacking of the binary models reduced the over-prediction, although more research is needed. The randomisation test proved to be a promising method for testing the performance of the stacked models, but other implementations may still be developed

Projected Loss of a Salamander Diversity Hotspot as a Consequence of Projected Global Climate Change

Background: Significant shifts in climate are considered a threat to plants and animals with significant physiological limitations and limited dispersal abilities. The southern Appalachian Mountains are a global hotspot for plethodontid salamander diversity. Plethodontids are lungless ectotherms, so their ecology is strongly governed by temperature and precipitation. Many plethodontid species in southern Appalachia exist in high elevation habitats that may be at or near their thermal maxima, and may also have limited dispersal abilities across warmer valley bottoms. Methodology/Principal Findings: We used a maximum-entropy approach (program Maxent) to model the suitable climatic habitat of 41 plethodontid salamander species inhabiting the Appalachian Highlands region (33 individual species and eight species included within two species complexes). We evaluated the relative change in suitable climatic habitat for these species in the Appalachian Highlands from the current climate to the years 2020, 2050, and 2080, using both the HADCM3 and the CGCM3 models, each under low and high CO 2 scenarios, and using two-model thresholds levels (relative suitability thresholds for determining suitable/unsuitable range), for a total of 8 scenarios per species. Conclusion/Significance: While models differed slightly, every scenario projected significant declines in suitable habitat within the Appalachian Highlands as early as 2020. Species with more southern ranges and with smaller ranges had larger projected habitat loss. Despite significant differences in projected precipitation changes to the region, projections did no

Targeting medication non-adherence behavior in selected autoimmune diseases: a systematic approach to digital health program development

Background 29 autoimmune diseases, including Rheumatoid Arthritis, gout, Crohn’s Disease, and Systematic Lupus Erythematosus affect 7.6-9.4% of the population. While effective therapy is available, many patients do not follow treatment or use medications as directed. Digital health and Web 2.0 interventions have demonstrated much promise in increasing medication and treatment adherence, but to date many Internet tools have proven disappointing. In fact, most digital interventions continue to suffer from high attrition in patient populations, are burdensome for healthcare professionals, and have relatively short life spans. Objective Digital health tools have traditionally centered on the transformation of existing interventions (such as diaries, trackers, stage-based or cognitive behavioral therapy programs, coupons, or symptom checklists) to electronic format. Advanced digital interventions have also incorporated attributes of Web 2.0 such as social networking, text messaging, and the use of video. Despite these efforts, there has not been little measurable impact in non-adherence for illnesses that require medical interventions, and research must look to other strategies or development methodologies. As a first step in investigating the feasibility of developing such a tool, the objective of the current study is to systematically rate factors of non-adherence that have been reported in past research studies. Methods Grounded Theory, recognized as a rigorous method that facilitates the emergence of new themes through systematic analysis, data collection and coding, was used to analyze quantitative, qualitative and mixed method studies addressing the following autoimmune diseases: Rheumatoid Arthritis, gout, Crohn’s Disease, Systematic Lupus Erythematosus, and inflammatory bowel disease. Studies were only included if they contained primary data addressing the relationship with non-adherence. Results Out of the 27 studies, four non-modifiable and 11 modifiable risk factors were discovered. Over one third of articles identified the following risk factors as common contributors to medication non-adherence (percent of studies reporting): patients not understanding treatment (44%), side effects (41%), age (37%), dose regimen (33%), and perceived medication ineffectiveness (33%). An unanticipated finding that emerged was the need for risk stratification tools (81%) with patient-centric approaches (67%). Conclusions This study systematically identifies and categorizes medication non-adherence risk factors in select autoimmune diseases. Findings indicate that patients understanding of their disease and the role of medication are paramount. An unexpected finding was that the majority of research articles called for the creation of tailored, patient-centric interventions that dispel personal misconceptions about disease, pharmacotherapy, and how the body responds to treatment. To our knowledge, these interventions do not yet exist in digital format. Rather than adopting a systems level approach, digital health programs should focus on cohorts with heterogeneous needs, and develop tailored interventions based on individual non-adherence patterns

dTip60 HAT Activity Controls Synaptic Bouton Expansion at the Drosophila Neuromuscular Junction

Background: Histone acetylation of chromatin plays a key role in promoting the dynamic transcriptional responses in neurons that influence the neuroplasticity linked to cognitive ability, yet the specific histone acetyltransferases (HATs) that create such epigenetic marks remain to be elucidated. Methods and Findings: Here we use the Drosophila neuromuscular junction (NMJ) as a well-characterized synapse model to identify HATs that control synaptic remodeling and structure. We show that the HAT dTip60 is concentrated both pre and post-synaptically within the NMJ. Presynaptic targeted reduction of dTip60 HAT activity causes a significant increase in synaptic bouton number that specifically affects type Is boutons. The excess boutons show a suppression of the active zone synaptic function marker bruchpilot, suggesting defects in neurotransmission function. Analysis of microtubule organization within these excess boutons using immunohistochemical staining to the microtubule associated protein futsch reveals a significant increase in the rearrangement of microtubule loop architecture that is required for bouton division. Moreover, a-tubulin acetylation levels of microtubules specifically extending into the terminal synaptic boutons are reduced in response to dTip60 HAT reduction. Conclusions: Our results are the first to demonstrate a causative role for the HAT dTip60 in the control of synaptic plasticity that is achieved, at least in part, via regulation of the synaptic microtubule cytoskeleton. These findings have implication