Design, data management, and population baseline characteristics of the PERFORM magnetic resonance imaging project

Quantitative information from magnetic resonance imaging (MRI) may substantiate clinical findings and provide additional insight into the mechanism of clinical interventions in therapeutic stroke trials. The PERFORM study is exploring the efficacy of terutroban versus aspirin for secondary prevention in patients with a history of ischemic stroke. We report on the design of an exploratory longitudinal MRI follow-up study that was performed in a subgroup of the PERFORM trial. An international multi-centre longitudinal follow-up MRI study was designed for different MR systems employing safety and efficacy readouts: new T2 lesions, new DWI lesions, whole brain volume change, hippocampal volume change, changes in tissue microstructure as depicted by mean diffusivity and fractional anisotropy, vessel patency on MR angiography, and the presence of and development of new microbleeds. A total of 1,056 patients (men and women ≥55 years) were included. The data analysis included 3D reformation, image registration of different contrasts, tissue segmentation, and automated lesion detection. This large international multi-centre study demonstrates how new MRI readouts can be used to provide key information on the evolution of cerebral tissue lesions and within the macrovasculature after atherothrombotic stroke in a large sample of patients

Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases

A aula e a sala de aula: um espaço-tempo de produção de conhecimento

Considera-se que a relação estabelecida entre professor e aluno é cultural, mas é também pedagógica, porque o espaço de convívio é mediado por conhecimentos que são, intencionalmente, ensinados e aprendidos. Nesse quadro, compreende-se que o exercício da docência deve, necessariamente, incluir momentos nos quais sejam feitas reflexão e crítica sobre as formas e o significado de ensinar, de trazer o outro para a sua perspectiva e com ele também aprender, momentos de experimentar situações desse acontecimento "feiticeiro" que se chama "sala de aula". São apresentados métodos e técnicas que possibilitam transformar estes momentos em oportunidades para construir conhecimento

Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma

Background Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) selumetinib or placebo, revealing trends to prolongation of progression-free survival (hazard ratio 0.75, P = 0.130), and improved response rates (32% vs 14%, P = 0.059) with docetaxel plus selumetinib. NRAS status did not associate with outcome. Here, the aim was to identify novel biomarkers of response to MEKi. Methods A MEK 6 gene signature was quantified using NanoString and correlated with clinical outcomes. Two components of the gene signature were investigated by gene silencing in BRAF/NRAS wild-type melanoma cells. Results In melanomas of patients on the selumetinib but not the placebo arm, two gene signature components, dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4), were expressed more highly in responders than non-responders. In vitro, ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib. In contrast, DUSP4-depleted cells showed enhanced cell survival and increased resistance to both selumetinib and trametinib. Conclusions ETV4 and DUSP4 associated with clinical response to docetaxel plus selumetinib. DUSP4 depletion induced MEKi resistance, suggesting that DUSP4 is not only a biomarker but also a mediator of MEKi sensitivity. Clinical Trial Registration DOC-MEK (EudraCT no: 2009-018153-23).</p

The Canadian Perinatal Network: a national network focused on threatened preterm birth at 22 to 28 weeks' gestation.

OBJECTIVE: The Canadian Perinatal Network (CPN) maintains an ongoing national database focused on threatened very preterm birth. The objective of the network is to facilitate between-hospital comparisons and other research that will lead to reductions in the burden of illness associated with very preterm birth. METHODS: Women were included in the database if they were admitted to a participating tertiary perinatal unit at 22+0 to 28+6 weeks' gestation with one or more conditions most commonly responsible for very preterm birth, including spontaneous preterm labour with contractions, incompetent cervix, prolapsing membranes, preterm prelabour rupture of membranes, gestational hypertension, intrauterine growth restriction, or antepartum hemorrhage. Data were collected by review of maternal and infant charts, entered directly into standardized electronic data forms and uploaded to the CPN via a secure network. RESULTS: Between 2005 and 2009, the CPN enrolled 2524 women from 14 hospitals including those with preterm labour and contractions (27.4%), short cervix without contractions (16.3%), prolapsing membranes (9.4%), antepartum hemorrhage (26.1%), and preterm prelabour rupture of membranes (23.0%). The mean gestational age at enrolment was 25.9 ± 1.9 weeks and the mean gestation age at delivery was 29.9 ± 5.1 weeks; 57.0% delivered at < 29 weeks and 75.4% at < 34 weeks. Complication rates were high and included serious maternal complications (26.7%), stillbirth (8.2%), neonatal death (16.3%), neonatal intensive care unit admission (60.7%), and serious neonatal morbidity (35.0%). CONCLUSION: This national dataset contains detailed information about women at risk of very preterm birth. It is available to clinicians and researchers who are working with one or more CPN collaborators and who are interested in studies relating processes of care to maternal or perinatal outcomes