Methodological challenges when evaluating potential off-label prescribing of drugs using electronic health care databases: A case study of dabigatran etexilate in Europe.

PURPOSE: To report and discuss estimated prevalence of potential off-label use and associated methodological challenges using a case study of dabigatran. METHODS: Observational, cross-sectional study using 3 databases with different types of clinical information available: Cegedim Strategic Data Longitudinal Patient Database (CSD-LPD), France (cardiologist panel, n = 1706; general practitioner panel, n = 2813; primary care data); National Health Databases, Denmark (n = 28 619; hospital episodes and dispensed ambulatory medications); and Clinical Practice Research Datalink (CPRD), UK (linkable to Hospital Episode Statistics [HES], n = 2150; not linkable, n = 1285; primary care data plus hospital data for HES-linkable patients). STUDY PERIOD: August 2011 to August 2015. Two definitions were used to estimate potential off-label use: a broad definition of on-label prescribing using codes for disease indication (eg, atrial fibrillation [AF]), and a restrictive definition excluding patients with conditions for which dabigatran is not indicated (eg, valvular AF). RESULTS: Prevalence estimates under the broad definition ranged from 5.7% (CPRD-HES) to 34.0% (CSD-LPD) and, under the restrictive definition, from 17.4% (CPRD-HES) to 44.1% (CSD-LPD). For the majority of potential off-label users, no diagnosis potentially related to anticoagulant use was identified. Key methodological challenges were the limited availability of detailed clinical information, likely leading to overestimation of off-label use, and differences in the information available, which may explain the disparate prevalence estimates across data sources. CONCLUSIONS: Estimates of potential off-label use should be interpreted cautiously due to limitations in available information. In this context, CPRD HES-linkable estimates are likely to be the most accurate.

The Drosophila Toll pathway controls but does not clear Candida glabrata infections.

The pathogenicity of Candida glabrata to patients remains poorly understood for lack of convenient animal models to screen large numbers of mutants for altered virulence. In this study, we explore the minihost model Drosophila melanogaster from the dual perspective of host and pathogen. As in vertebrates, wild-type flies contain C. glabrata systemic infections yet are unable to kill the injected yeasts. As for other fungal infections in Drosophila, the Toll pathway restrains C. glabrata proliferation. Persistent C. glabrata yeasts in wild-type flies do not appear to be able to take shelter in hemocytes from the action of the Toll pathway, the effectors of which remain to be identified. Toll pathway mutant flies succumb to injected C. glabrata. In this immunosuppressed background, cellular defenses provide a residual level of protection. Although both the Gram-negative binding protein 3 pattern recognition receptor and the Persephone protease-dependent detection pathway are required for Toll pathway activation by C. glabrata, only GNBP3, and not psh mutants, are susceptible to the infection. Both Candida albicans and C. glabrata are restrained by the Toll pathway, yet the comparative study of phenoloxidase activation reveals a differential activity of the Toll pathway against these two fungal pathogens. Finally, we establish that the high-osmolarity glycerol pathway and yapsins are required for virulence of C. glabrata in this model. Unexpectedly, yapsins do not appear to be required to counteract the cellular immune response but are needed for the colonization of the wild-type host.

Drosophila mir-9a regulates wing development via fine-tuning expression of the LIM only factor, dLMO.

MicroRNAs are short non-coding endogenous RNAs that are implicated in regulating various aspects of plants and animal development, however their functions in organogenesis are largely unknown. Here we report that mir-9a belonging to the mir-9 family, regulates Drosophila wing development through a functional target site in the 3' untranslated region of the Drosophila LIM only protein, dLMO. dLMO is a transcription cofactor, that directly inhibits the activity of Apterous, the LIM-HD factor required for the proper dorsal identity of the wings. Deletions of the 3' untranslated region, including the mir-9a site, generate gain-of-function dLMO mutants (Beadex) associated with high levels of dLMO mRNA and protein. Beadex mutants lack wing margins, a phenotype also observed in null mir-9a mutants. We found that mir-9a and dLMO are co-expressed in wing discs and interact genetically for controlling wing development. Lack of mir-9a results in overexpression of dLMO, while gain-of-function mir-9a mutant suppresses dLMO expression. These data indicate that a function of mir-9a is to ensure the appropriate stoichiometry of dLMO during Drosophila wing development. The mir-9a binding site is conserved in the human counterpart LMO2, the T-cell acute leukemia oncogene, suggesting that mir-9 might apply a similar strategy to maintain LMO2 expression under a detrimental threshold.

No Evidence of Off-label Use of Olodaterol and Indacaterol in Denmark, France, and the Netherlands: A Drug Utilization Study.

To characterize the use of olodaterol and indacaterol in clinical practice and to quantify the off-label use in asthma. Drug utilization study of new users of olodaterol or indacaterol between 2014 and 2017 in the PHARMO Database Network in the Netherlands, the Danish population registers, and the IMS Real-World Evidence Longitudinal Patient Database panels in France. On-label use was defined as use among adults with a recorded diagnosis of COPD. Off-label use was defined as use among adults with a recorded diagnosis of asthma without a recorded diagnosis of COPD or as use among patients aged ≤18 years. Potential off-label use was defined as no recorded diagnosis of either COPD or asthma. The study included 4,158 new users of olodaterol and 9,966 new users of indacaterol. Prevalence of off-label use ranged from 3.5% for both drugs to 12.4% for olodaterol and 11.9% for indacaterol. Prevalence of on-label use ranged from 47.8% to 77.7% for olodaterol and from 28.7% to 70.1% for indacaterol. The remaining new users of olodaterol and indacaterol were classified as potential off-label users, with prevalence ranging from 17.3% to 48.6% for olodaterol and from 20.5% to 66.6% for indacaterol. This study provides no evidence of a major concern in Europe for olodaterol or indacaterol for off-label use in asthma or for pediatric use.

Drosophila dLMO-PA isoform acts as an early activator of achaete/scute proneural expression.

The Drosophila bHLH proneural factors Achaete (Ac) and Scute (Sc) are expressed in clusters of cells (proneural clusters), providing the cells with the potential to develop a neural fate. Mediodorsal proneural patterning is mediated through the GATA transcription factor Pannier (Pnr) that activates ac/sc directly through binding to the dorsocentral (DC) enhancer of ac/sc. Besides, the Gfi transcription factor Senseless (Sens), a target of Ac/Sc, synergizes with ac/sc in the presumptive sensory organ precursors (SOPs). Here we investigate, through new genetic tools, the function of dLMO, the Drosophila LIM only transcription factor that was already known to control wing development. We show that dLMO gene encodes two isoforms, dLMO-RA and dLMO-RB. dLMO null and dLMO-RA(-) deletions have similar phenotypes, lacking thoracic and wing margin sensory organs (SO), while dLMO-RB(-) deletion has normal SOs. At early stages, dLMO-RA is expressed in proneural clusters, however later it is excluded from the SOPs. We found that dLMO functions as a Pnr coactivator to promote ac/sc expression. In the late SOPs, where dLMO-PA is not expressed, Pnr participates to the Sens-dependent regulation of ac/sc. Taken together these results suggest that dLMO-PA is the major isoform that is required for early activation of ac/sc expression.

Initiation and continuation of oral anticoagulant prescriptions for stroke prevention in non-valvular atrial fibrillation: A cohort study in primary care in France.

BACKGROUND: Oral anticoagulants are prescribed in non-valvular atrial fibrillation for stroke prevention; however, little is known about the current management of anticoagulation in France, particularly given the availability of non-vitamin K antagonist oral anticoagulants in recent years. AIMS: To describe the characteristics of patients prescribed oral anticoagulants, and assess treatment persistence in French primary care. METHODS: We conducted a cohort study of patients with non-valvular atrial fibrillation, who were newly prescribed oral anticoagulants between 1 January 2014 and 31 January 2016, using French primary care data (IMS Longitudinal Patient Database). Adjusting for baseline characteristics, risk of non-persistence (switch or discontinuation) was compared using Cox regression. RESULTS: Of 4111 patients, 1710 were newly prescribed vitamin K antagonists, 1257 rivaroxaban, 744 apixaban and 400 dabigatran. The median age was 76 years, and 57.5% were male. History of hypertension was the most common co-morbidity (68.1%). Compared with vitamin K antagonists, non-persistence was higher with rivaroxaban (hazard ratio: 1.28; 95% confidence interval: 1.13-1.45) and dabigatran (hazard ratio: 1.42; 95% confidence interval: 1.20-1.69) and similar with apixaban (hazard ratio: 1.12; 95% confidence interval: 0.96-1.32). CONCLUSIONS: Non-persistence (treatment discontinuation or switch) with vitamin K antagonists was lower than with rivaroxaban and dabigatran in French primary care; however, non-persistence with the newest drug, apixaban, was similar to vitamin K antagonists. Larger studies with longer follow-up are needed to support these findings. This study is registered on ClinicalTrials.gov (NCT02488421).