TrpA1 Regulates Thermal Nociception in Drosophila

Pain is a significant medical concern and represents a major unmet clinical need. The ability to perceive and react to tissue-damaging stimuli is essential in order to maintain bodily integrity in the face of environmental danger. To prevent damage the systems that detect noxious stimuli are therefore under strict evolutionary pressure. We developed a high-throughput behavioral method to identify genes contributing to thermal nociception in the fruit fly and have reported a large-scale screen that identified the Ca2+ channel straightjacket (stj) as a conserved regulator of thermal nociception. Here we present the minimal anatomical and neuronal requirements for Drosophila to avoid noxious heat in our novel behavioral paradigm. Bioinformatics analysis of our whole genome data set revealed 23 genes implicated in Ca2+ signaling that are required for noxious heat avoidance. One of these genes, the conserved thermoreceptor TrpA1, was confirmed as a bona fide “pain” gene in both adult and larval fly nociception paradigms. The nociceptive function of TrpA1 required expression within the Drosophila nervous system, specifically within nociceptive multi-dendritic (MD) sensory neurons. Therefore, our analysis identifies the channel TRPA1 as a conserved regulator of nociception

A competing-risk approach to modelling length of stay in severe malaria patients in South-East Asia and the implications for planning of hospital services

Malaria burdens global health systems, and management with limited resources requires robust treatment guidelines and comprehensive planning. Expected length of stay (LOS) is useful in health-system planning, and factors influencing it can be targeted to reduce admission time and optimise service delivery.A secondary survival analysis of 1217 adult severe malaria patients from the South-East Asia Quinine Artesunate Malaria Trial, using a competing-risk approach.Median LOS was five days and time to discharge six days. 80% of patients were discharged, 70.2% within a week. 95.4% of deaths occurred within seven days. Compared to quinine, artesunate increased discharge incidence (subdistribution-hazard ratio 1.24 (1.09-1.40) p=0.001) and decreased incidence of death (0.60 (0.46-0.80) p<0.001). Cumulative incidence of discharge was decreased, and death increased, by low Glasgow coma scale (discharge: 1.08 (1.06-1.11) p<0.001, death: 0.85 (0.82-0.89) p<0.001), high blood urea-nitrogen (discharge: 0.99 (0.99-0.995) p<0.001, death: 1.00 (1.00-1.01) p=0.012), acidotic base-excess (discharge: 1.05 (1.03-1.06) p<0.001, death: 0.90 (0.88-0.93) p<0.001), and development of shock (discharge: 0.25 (0.13-0.47) p<0.001, death: 2.14 (1.46-3.12) p<0.001) or coma (discharge: 0.46 ( 0.32-0.65) p<0.001, death: 2.30 (1.58-3.36) p<0.001). Conventional Kaplan-Meier survival analysis overestimated cumulative incidence compared to competing-risk models.Clinical factors on admission and during hospitalisation influence LOS in severe malaria, offering targets to improve health and service efficiency. Artesunate has the potential to increase LOS, which should be accounted for in service-planning. Death in-hospital is a competing risk for discharge, and should be considered in LOS models to reduce overestimation of risk and misrepresentation of associations

Drug-Induced Progressive Multifocal Leukoencephalopathy: A Comprehensive Analysis of the WHO Adverse Drug Reaction Database

Objective To identify safety signals concerning the association between the use of various drug classes and the onset of progressive multifocal leukoencephalopathy (PML). Methods All reports containing suspected or interacting PML-related or leukoencephalopathy-related drugs, held in the World Health Organization spontaneous individual case safety reports database as at 1 September 2014, were retrieved.Weidentified safety signals by analysing the drug– reaction pairs, using the reporting odds ratio as a measure of disproportionality. A safety signal was defined if a drug was reported more than twice in PML cases with a reporting odds ratio[2 and a lower 95 % confidence limit[1. Results We retrieved 2452 reports associated with PML (N = 1612), leukoencephalopathy (N = 835) or both (N = 5), corresponding to 343 different drugs. PML was reported similarly in male and female adults (18–64 years), and almost 30 % of the cases had a fatal outcome. The most frequent Anatomical Therapeutic Chemical (ATC) classification groups concerned antineoplastic agents (23.5 %), antivirals for systemic use (10.1 %) or immunostimulants (4.6 %). Significant disproportionality was found for 88 drugs in the overall analysis (of cases with ‘progressive multifocal leukoencephalopathy’ or ‘leukoencephalopathy’ as the Preferred Term), and a new safety signal was identified for 59 active substances (e.g. muromonab-CD3, basiliximab and antithymocyte Ig), as no information on a possible risk of PML was acknowledged in their Summary of Product Characteristics documents. Some safety signals were confirmed also after sensitivity analysis adjustment for several confounding factors (underlying diseases and considering only ‘progressive multifocal leukoencephalopathy’ as the Preferred Term). Conclusion We report a possible association between several drugs and PML that has not been previously described. In addition, we have confirmed previously reported signals in a number of drugs. We highlight the need for follow-up by regulatory agencies