Reports of substandard medicines: a lexicographic analysis of the Brazilian Health Surveillance Report System

Regulatory agencies are responsible for collecting and evaluating spontaneous reports of suspected problems related to medications, including those from substandard medicines (SM). Objectives: The aim was to evaluate the profile of SM reports submitted to the Brazilian Health Surveillance Notification System (Notivisa) and classify these reports objectively by means of lexicographic analysis. Methods: Was extracted all SM reports available in Notivisa during the period 1 January 2007 to 31 December 2017. Descriptive statistics were performed and the reasons for SM reporting were standardized (using OpenRefine and Microsoft Excel). The following analyses were performed using IRAMuTeQ 0.7 alpha2: lexicographic analysis to obtain the frequency of active words; descending hierarchical classification (DHC) to categorize the active words into lexical classes; factorial correspondence analysis (FCA) to obtain graphs of the classes. Approved by the Ethics Committee of the Hospital do Trabalhador/SES/PR CAAE 81873417.3.0000.5225 (protocol number: 2.506.594). Results: A total of 61,775 reports were analyzed, most of them reported by hospitals (46%). The DHC of the reasons for SM produced four classes visualized in the FCA: (i) packaging problems (16%) mainly leakages/opening issues; (ii) inadequate drug identification (22%), such as illegible label information; (iii) stability and contamination issues (11%) such as presence of particles; (iv) damaged tablets/blisters (23%) mainly broken tablets. Most SM (52%) were solutions for parenteral use; sodium chloride (9%), glucose and dipyrone (3%) were the products with most complaints. Conclusions: The reasons for SM reporting can be objectively classified into classes that represent the main problems submitted to Notivisa. This classification could guide the standardization of SM reporting and contribute to improving surveillance reporting systems worldwide

Inertia based microfluidic capture and characterisation of circulating tumour cells for the diagnosis of lung cancer

Background: Routine clinical application of circulating tumour cells (CTCs) for blood based diagnostics is yet to be established. Despite growing evidence of their clinical utility for diagnosis, prognosis and treatment monitoring, the efficacy of a robust platform and universally accepted diagnostic criteria remain uncertain. We evaluate the diagnostic performance of a microfluidic CTC isolation platform using cytomorphologic criteria in patients undergoing lung cancer surgery. Methods: Blood was processed from 51 patients undergoing surgery for known or suspected lung cancer using the ClearBridge ClearCell FX systemTM (ClearBridge Biomedics, Singapore). Captured cells were stained on slides with haematoxylin and eosin (H&E) and independently assessed by two pathologist teams. Diagnostic performance was evaluated against the pathologists reported diagnosis of cancer from surgically obtained specimens. Results: Cancer was diagnosed in 43.1% and 54.9% of all cases. In early stage primary lung cancer, between the two reporting teams, a positive diagnosis of CTCs was made for 50% and 66.7% of patients. The agreement between the reporting teams was 80.4%, corresponding to a kappa-statistic of 0.61±0.11 (P<0.001), indicating substantial agreement. Sensitivity levels for the two teams were calculated as 59% (95% CI, 41–76%) and 41% (95% CI, 24–59%), with a specificity of 53% for both. Conclusions: The performance of the tested microfluidic antibody independent device to capture CTCs using standard cytomorphological criteria provides the potential of a diagnostic blood test for lung cancer

Metabarcoding of insect-associated fungal communities: a comparison of internal transcribed spacer (ITS) and large-subunit (LSU) rRNA markers

Full taxonomic characterisation of fungal communities is necessary for establishing ecological associations and early detection of pathogens and invasive species. Complex communities of fungi are regularly characterised by metabarcoding using the Internal Transcribed Spacer (ITS) and the Large-Subunit (LSU) gene of the rRNA locus, but reliance on a single short sequence fragment limits the confidence of identification. Here we link metabarcoding from the ITS2 and LSU D1-D2 regions to characterise fungal communities associated with bark beetles (Scolytinae), the likely vectors of several tree pathogens. Both markers revealed similar patterns of overall species richness and response to key variables (beetle species, forest type), but identification against the respective reference databases using various taxonomic classifiers revealed poor resolution towards lower taxonomic levels, especially the species level. Thus, Operational Taxonomic Units (OTUs) could not be linked via taxonomic classifiers across ITS and LSU fragments. However, using phylogenetic trees (focused on the epidemiologically important Sordariomycetes) we placed OTUs obtained with either marker relative to reference sequences of the entire rRNA cistron that includes both loci and demonstrated the largely similar phylogenetic distribution of ITS and LSU-derived OTUs. Sensitivity analysis of congruence in both markers suggested the biologically most defensible threshold values for OTU delimitation in Sordariomycetes to be 98% for ITS2 and 99% for LSU D1-D2. Studies of fungal communities using the canonical ITS barcode require corroboration across additional loci. Phylogenetic analysis of OTU sequences aligned to the full rRNA cistron shows higher success rate and greater accuracy of species identification compared to probabilistic taxonomic classifiers

The CannTeen study: verbal episodic memory, spatial working memory, and response inhibition in adolescent and adult cannabis users and age-matched controls

BACKGROUND: Preclinical and human studies suggest that adolescent cannabis use may be associated with worse cognitive outcomes than adult cannabis use. We investigated the associations between chronic cannabis use and cognitive function in adolescent and adult cannabis users and controls. We hypothesised user-status would be negatively associated with cognitive function and this relationship would be stronger in adolescents than adults. METHODS: As part of the 'CannTeen' project, this cross-sectional study assessed cognitive performance in adolescent cannabis users (n = 76; 16-17-year-olds), adolescent controls (n = 63), adult cannabis users (n = 71; 26-29-year-olds) and adult controls (n = 64). Users used cannabis 1-7 days/week. Adolescent and adult cannabis users were matched on cannabis use frequency (4 days/week) and time since last use (2.5 days). Verbal episodic memory (VEM) was assessed using the prose recall task, spatial working memory (SWM) was assessed using the spatial n-back task, and response inhibition was assessed with the stop-signal task. Primary outcome variables were: delayed recall, 3-back discriminability, and stop signal reaction time, respectively. RESULTS: Users had worse VEM than controls (F(1,268) = 7.423, p = 0.007). There were no significant differences between user-groups on SWM or response inhibition. Null differences were supported by Bayesian analyses. No significant interactions between age-group and user-group were found for VEM, SWM, or response inhibition. CONCLUSIONS: Consistent with previous research, there was an association between chronic cannabis use and poorer VEM, but chronic cannabis use was not associated with SWM or response inhibition. We did not find evidence for heightened adolescent vulnerability to cannabis-related cognitive impairment

Non-unitary Leptonic Mixing and Leptogenesis

We investigate the relation between non-unitarity of the leptonic mixing matrix and leptogenesis. We discuss how all parameters of the canonical type-I seesaw mechanism can, in principle, be reconstructed from the neutrino mass matrix and the deviation of the effective low-energy leptonic mixing matrix from unitary. When the mass M' of the lightest right-handed neutrino is much lighter than the masses of the others, we show that its decay asymmetries within flavour-dependent leptogenesis can be expressed in terms of two contributions, one depending on the unique dimension five (d=5) operator generating neutrino masses and one depending on the dimension six (d=6) operator associated with non-unitarity. In low-energy seesaw scenarios where small lepton number violation explains the smallness of neutrino masses, the lepton number conserving d=6 operator contribution generically dominates over the d=5 operator contribution which results in a strong enhancement of the flavour-dependent decay asymmetries without any resonance effects. To calculate the produced final baryon asymmetry, the flavour equilibration effects directly related to non-unitarity have to be taken into account. In a simple realization of this non-unitarity driven leptogenesis, the lower bound on M' is found to be about 10^8 GeV at the onset of the strong washout regime, more than one order of magnitude below the bound in "standard" thermal leptogenesis.Comment: 19 pages, REVTeX4, 2 eps and 2 axodraw figure

Sociodemographic, Attitudinal, and Behavioral Correlates of Using Nutrition, Weight Loss, and Fitness Websites : An Online Survey

Background: Nutrition, diet, and fitness are among the most searched health topics by internet users. Besides that, health-related internet users are diverse in their motivations and individual characteristics. However, little is known about the individual characteristics associated with the usage of nutrition, weight loss, and fitness websites. Objective: The aim of this study was to examine the individual factors associated with the usage of nutrition, weight loss, and fitness websites. Methods: An invitation to an online survey was published on 65 websites and discussion forums. In total, we employed data from 623 participants (aged 13 to 39 years, mean 24.11 [SD 5.26]). The measures included frequency of usage of nutrition, weight loss and fitness websites, excessive exercise, eating disorder symptomatology, internalization of the beauty ideal, weight status, and perceived online social support. Participants’ data were used as predictors in a base linear regression model. Results: The final model had an acceptable fit (X210 =14.1; P=.17; root mean square error of approximation=0.03; comparative fit index=0.99; Tucker-Lewis index=0.99). Positive associations were found between usage of (1) nutrition websites and being female, higher levels of excessive exercise, and perceived online social support; (2) weight loss websites and excessive exercise, internalization, being female, eating disorder symptomatology, and being overweight or obese; and (3) fitness websites and levels of excessive exercise, internalization, and frequency of internet use. Conclusions: The results highlighted the importance of individual differences in the usage of health-related websites

Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Rapid Diagnostic Algorithms as a Screening Tool for Tuberculosis: An Assessor Blinded Cross-Sectional Study

Background: A major obstacle to effectively treat and control tuberculosis is the absence of an accurate, rapid, and low-cost diagnostic tool. A new approach for the screening of patients for tuberculosis is the use of rapid diagnostic classification algorithms. Methods: We tested a previously published diagnostic algorithm based on four biomarkers as a screening tool for tuberculosis in a Central European patient population using an assessor-blinded cross-sectional study design. In addition, we developed an improved diagnostic classification algorithm based on a study population at a tertiary hospital in Vienna, Austria, by supervised computational statistics. Results: The diagnostic accuracy of the previously published diagnostic algorithm for our patient population consisting of 206 patients was 54% (CI: 47%–61%). An improved model was constructed using inflammation parameters and clinical information. A diagnostic accuracy of 86% (CI: 80%–90%) was demonstrated by 10-fold cross validation. An alternative model relying solely on clinical parameters exhibited a diagnostic accuracy of 85% (CI: 79%–89%). Conclusion: Here we show that a rapid diagnostic algorithm based on clinical parameters is only slightly improved by inclusion of inflammation markers in our cohort. Our results also emphasize the need for validation of new diagnostic algorithms in different settings and patient populations

Systemic Risk and Default Clustering for Large Financial Systems

As it is known in the finance risk and macroeconomics literature, risk-sharing in large portfolios may increase the probability of creation of default clusters and of systemic risk. We review recent developments on mathematical and computational tools for the quantification of such phenomena. Limiting analysis such as law of large numbers and central limit theorems allow to approximate the distribution in large systems and study quantities such as the loss distribution in large portfolios. Large deviations analysis allow us to study the tail of the loss distribution and to identify pathways to default clustering. Sensitivity analysis allows to understand the most likely ways in which different effects, such as contagion and systematic risks, combine to lead to large default rates. Such results could give useful insights into how to optimally safeguard against such events.Comment: in Large Deviations and Asymptotic Methods in Finance, (Editors: P. Friz, J. Gatheral, A. Gulisashvili, A. Jacqier, J. Teichmann) , Springer Proceedings in Mathematics and Statistics, Vol. 110 2015

New physics searches at near detectors of neutrino oscillation experiments

We systematically investigate the prospects of testing new physics with tau sensitive near detectors at neutrino oscillation facilities. For neutrino beams from pion decay, from the decay of radiative ions, as well as from the decays of muons in a storage ring at a neutrino factory, we discuss which effective operators can lead to new physics effects. Furthermore, we discuss the present bounds on such operators set by other experimental data currently available. For operators with two leptons and two quarks we present the first complete analysis including all relevant operators simultaneously and performing a Markov Chain Monte Carlo fit to the data. We find that these effects can induce tau neutrino appearance probabilities as large as O(10^{-4}), which are within reach of forthcoming experiments. We highlight to which kind of new physics a tau sensitive near detector would be most sensitive.Comment: 20 pages, 2 figures, REVTeX