Genetic mutations in pfcrt and pfmdr1 at the time of artemisinin combination therapy introduction in South Pacific islands of Vanuatu and Solomon Islands

Background: Chloroquine (CQ), alone or in combination with sulphadoxine-pyrimethamine, was widely used for the treatment of Plasmodium falciparum and Plasmodium vivax for several decades in both Vanuatu and Solomon Islands prior to the introduction of artemether-lumefantrine (AL) in 2008. However, the effect of chloroquine selection on parasite population, which may affect the efficacy of lumefantrine or other partner drugs of artemisinin, has not been well assessed. This study aims to provide baseline data on molecular markers (pfcrt and pfmdr1), along with the origins of pfcrt, prior to the introduction of AL. Methods: Blood spots were obtained from epidemiological surveys conducted on Tanna Island, Tafea Province, Vanuatu and Temotu Province, Solomon Islands in 2008. Additional samples from Malaita Province, Solomon Islands were collected as part of an artemether-lumefantrine efficacy study in 2008. Plasmodium falciparum pfcrt and pfmdr1 genes were examined for polymorphisms. Microsatellite markers flanking pfcrt were also examined to ascertain origins of CQ resistance. Results: Pfcrt analysis revealed 100% of parasites from Tafea Province, Vanuatu and Malaita Province, Solomon Islands and 98% of parasites from Temotu Province, Solomon Islands carried the K76T polymorphism that confers CQ resistance. Comparison of pfcrt allelic patterns and microsatellite markers flanking pfcrt revealed six haplotypes with more than 70% of isolates possessing haplotypes very similar to those observed in Papua New Guinea. The dominant (98.5%) pfmdr1 allele across all island groups was YYCND. Conclusions: Prior to the introduction of AL in the Solomon Islands and Vanuatu, P. falciparum isolates possessed point mutations known to confer CQ resistance and possibly associated with a decreased susceptibility to quinine and halofantrine, but an increased susceptibility to artemisinin and lumefantrine. Overall, pfcrt allelic types and the flanking microsatellite markers exhibited similarities to those of Papua New Guinea, suggesting these parasites share a common ancestry. The current use of AL for both P. falciparum and P. vivax infections will enable changes in these markers, in the absence of CQ pressure, to be monitored

A large proportion of asymptomatic Plasmodium infections with low and sub-microscopic parasite densities in the low transmission setting of Temotu Province, Solomon Islands: challenges for malaria diagnostics in an elimination setting

Background: Many countries are scaling up malaria interventions towards elimination. This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities. Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination. A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Bullying escolar: um fenômeno multifacetado

School bullying can involve children in different ways, making them play different roles, among them, victims, bullies and bully-victims. The aim of this study was to describe how bullying occurs in high social vulnerability schools of Florianópolis metropolitan area and the roles played by students in this phenomenon. Overall, 409 children and adolescents from the 3rd to 5th grades and of two public elementary schools aged 8-16 years (X = 11.14) participated in this study. As a tool, the Olweus Questionnaire adapted to the Brazilian population was used. For data analysis, descriptive statistics and inferential statistics were applied by the Mann Whitney and Kruskal Wallis tests. As for results, 29.8% of boys and 40.5% of girls reported being victims; 32.3% of boys and 24.6% of girls reported being bullies. Victims were the most willing to help a colleague who is suffering from bullying (X = 1.54; p> 0.001), even if they do not know the victims (X = 1.57; p> 0.004). Bullies are differentiated from the group that does not participate (X = 1.73) and the group of victims (X = 2.34), being those who felt less alone (x = 1.47; p> 0.001). It was concluded that the information obtained in this study is indispensable in the search for alternatives to reduce school bullying. The strengthening of relations between school and students and a better preparation of teachers and school staff are extremely necessary to try to minimize the effects of risk factors to which these children are exposed and consequently violence at school.O bullying escolar pode envolver crianças de diferentes maneiras, fazendo com que essas assumam papéis diferenciados. Dentre estes, têm-se vítimas, agressores e vítimas-agressoras. O objetivo deste estudo foi descrever como ocorre o bullying em escolas de alta vulnerabilidade social da Grande Florianópolis e os papéis assumidos pelos alunos nesse fenômeno. Quanto ao método, participaram 409 crianças e adolescentes do terceiro ao quinto ano e da quarta à sexta série do ensino fundamental, de duas escolas públicas municipais, com idades entre 8 e 16 anos (X=11,14). Como instrumento, utilizou-se o Questionário de Olweus adaptado à população brasileira. Para a análise dos dados, empregaram-se a estatística descritiva e estatística inferencial por meio dos testes Mann Whitney e Kruskal Wallis. Quanto aos resultados, 29,8% dos meninos e 40,5% das meninas relataram terem sido vítimas; já 32,3% dos meninos e 24,6% das meninas relataram terem sido agressores. As vítimas foram as que se mostraram mais dispostas a ajudar como podem um colega que esteja sofrendo agressão (X=1,54; p>0,001), mesmo que não o conheçam (X=1,57; p>0,004). Em contrapartida, os agressores se diferenciaram do grupo que não participa (X=1,73) e do grupo das vítimas (X=2,34), sendo aqueles que menos se sentiram sozinhos (X=1,47; p>0,001). Concluiu-se que as informações obtidas neste estudo são indispensáveis na busca de alternativas para redução do bullying escolar. O fortalecimento das relações entre escola e alunos, e um maior preparo dos professores e funcionários são extremamente necessários para tentar minimizar os efeitos dos fatores de risco a que essas crianças estão expostas e consequentemente a violência na escola.CAPES - Proc. nº 0815/14-4CIEC - Centro de Investigação em Estudos da Criança, IE, UMinho (UI 317 da FCT)Projeto Estratégico da FCT: UID/CED/00317/201

Proceedings of Patient Reported Outcome Measure’s (PROMs) Conference Oxford 2017: Advances in Patient Reported Outcomes Research

A33-Effects of Out-of-Pocket (OOP) Payments and Financial Distress on Quality of Life (QoL) of People with Parkinson’s (PwP) and their Carer

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead