Serious Adverse Drug Reactions and Safety Signals in Children: A Nationwide Database Study

Children are more exposed to inappropriate medicine use and its consequent harms. Spontaneous reporting of suspected Serious Adverse Drug Reactions (SADR) increases knowledge and prevention of pharmacotherapy risk. Disproportionality measures are useful to quantify unexpected safety issues associated with a given drug-event pair (signals of disproportionality). This cross-sectional study aimed to assess SADR reporting and safety signals for Brazilian children from 0-12 years old, notified between January 2008 and December 2013 from the Brazilian Surveillance Agency (Notivisa). Information from serious reports (gender and age of the patient, event description, suspected drug) was included. Disproportionality analysis based on Reporting Odds Ratios with a confidence interval of 95% was conducted to identify possible signals of disproportionate reporting (SDR). Almost 30% of 1,977 suspected SADR was related to babies (0-1-year-old). 69% of reports happened with intravenous dosage forms, and 35% of suspected SADR involved off label use according to age. Laronidase, miglustat, imipenem/cilastatin, and clofarabine were involved in six or more suspected deaths among 75 deaths reported. There were 107 SDRs, of which 16 events (15%) were not described in the product labels. There was a relatively higher number of SADRs in Brazilian children compared with studies from other countries. SDRs found, (especially drug-event pairs 'imipenen/cilastatin-pneumonia' and 'laronidase-respiratory insufficiency') should be investigated more. The reports of SADR with IV dosage forms and OL drug use suggest the need for drug research and the use of better dosage forms for children in Brazil

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Perfil dos ensaios clínicos envolvendo crianças brasileiras

Resumo: Este estudo visou a caracterizar os ensaios clínicos com medicamentos envolvendo crianças e adolescentes brasileiros, registrados nas bases de dados do Clinical Trials e da Registro Brasileiro de Ensaios Clínicos (ReBEC), entre os anos de 1994 e 2014. Apenas 462 ensaios clínicos envolveram brasileiros nessa faixa etária. A partir de 2003, houve aumento no número de registros, com expressiva queda em 2011. Dentre esses, 35,5% foram sediados no Brasil. Os ensaios clínicos internacionais foram majoritariamente conduzidos por empresas norte-americanas. Em ambos os casos, a indústria multinacional foi a principal fonte de apoio financeiro. Predominaram ensaios clínicos de fase III com antivirais em formas farmacêuticas injetáveis e sólidas orais. Os ensaios clínicos nacionais apresentaram maior variação quanto às formas farmacêuticas e maior porcentual de formulações líquidas investigadas, em comparação aos internacionais. Além da forte dependência externa para a realização dos ensaios clínicos, destacou-se o desafio para o cuidado pediátrico no Brasil, que apresenta peculiaridades epidemiológicas em um ambiente propício ao uso de medicamentos não licenciados para crianças

The taxonomic impediment: a shortage of taxonomists, not the lack of technical approaches.

Engel, Michael S, Ceríaco, Luis M P, Daniel, Gimo M, Dellapé, Pablo M, Löbl, Ivan, Marinov, Milen, Reis, Roberto E, Young, Mark T, Dubois, Alain, Agarwal, Ishan, Lehmann A., Pablo, Alvarado, Mabel, Alvarez, Nadir, Andreone, Franco, Araujo-Vieira, Katyuscia, Ascher, John S, Baêta, Délio, Baldo, Diego, Bandeira, Suzana A, Barden, Phillip, Barrasso, Diego A, Bendifallah, Leila, Bockmann, Flávio A, Böhme, Wolfgang, Borkent, Art, Brandão, Carlos R F, Busack, Stephen D, Bybee, Seth M, Channing, Alan, Chatzimanolis, Stylianos, Christenhusz, Maarten J M, Crisci, Jorge V, D'elía, Guillermo, Da Costa, Luis M, Davis, Steven R, De Lucena, Carlos Alberto S, Deuve, Thierry, Fernandes Elizalde, Sara, Faivovich, Julián, Farooq, Harith, Ferguson, Adam W, Gippoliti, Spartaco, Gonçalves, Francisco M P, Gonzalez, Victor H, Greenbaum, Eli, Hinojosa-Díaz, Ismael A, Ineich, Ivan, Jiang, Jianping, Kahono, Sih, Kury, Adriano B, Lucinda, Paulo H F, Lynch, John D, Malécot, Valéry, Marques, Mariana P, Marris, John W M, Mckellar, Ryan C, Mendes, Luis F, Nihei, Silvio S, Nishikawa, Kanto, Ohler, Annemarie, Orrico, Victor G D, Ota, Hidetoshi, Paiva, Jorge, Parrinha, Diogo, Pauwels, Olivier S G, Pereyra, Martín O, Pestana, Lueji B, Pinheiro, Paulo D P, Prendini, Lorenzo, Prokop, Jakub, Rasmussen, Claus, Rödel, Mark-Oliver, Rodrigues, Miguel Trefaut, Rodríguez, Sara M, Salatnaya, Hearty, Sampaio, Íris, Sánchez-García, Alba, Shebl, Mohamed A, Santos, Bruna S, Solórzano-Kraemer, Mónica M, Sousa, Ana C A, Stoev, Pavel, Teta, Pablo, Trape, Jean-François, Dos Santos, Carmen Van-Dúnem, Vasudevan, Karthikeyan, Vink, Cor J, Vogel, Gernot, Wagner, Philipp, Wappler, Torsten, Ware, Jessica L, Wedmann, Sonja, Zacharie, Chifundera Kusamba (2021): EDITORIAL The taxonomic impediment: a shortage of taxonomists, not the lack of technical approaches. Zoological Journal of the Linnean Society 193 (2): 381-387, DOI: 10.1093/zoolinnean/zlab072, URL: https://academic.oup.com/zoolinnean/article/193/2/381/637438

NEOTROPICAL CARNIVORES: a data set on carnivore distribution in the Neotropics

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589