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

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Sensitivity and Specificity of an Executive Function Screener at Identifying Children With ADHD and Reading Disability.

OBJECTIVE: This study evaluated the sensitivity/specificity of a global sum score (GSS) from the Behavior Assessment System for Children, Second Edition, Executive Function screener (BASC-2-EF) at classifying children with/without ADHD and/or reading disability (RD). METHOD: The BASC-2 Teacher/Parent Rating Scales (TRS/PRS) were completed for children (8-12 years old; 43.1% female) with no diagnosis ( n = 53), RD ( n = 34), ADHD ( n = 85), co-morbid RD/ADHD ( n = 36), and other diagnoses ( n = 15). Receiver operating characteristic (ROC) curve analyses evaluated the sensitivity/specificity of the BASC-2-EF GSS at discriminating between children with/without ADHD or RD. RESULTS: Area under the curve (AUC) scores indicated the sensitivity/specificity of the BASC-2-EF GSS at discriminating between children with/without ADHD (TRS: AUC = .831, p \u3c .001; PRS: AUC = .919, p \u3c .001), with/without RD (TRS: AUC = .724, p = .001; PRS: AUC = .615, p = .101), and with ADHD or RD through post hoc analysis (TRS: AUC = .674, p = .006; PRS: AUC = .819, p \u3c .001). CONCLUSION: The findings support utilizing the BASC-2-EF GSS when differentiating ADHD from RD and typical development

A single-dose live-attenuated vaccine prevents Zika virus pregnancy transmission and testis damage

Esta pesquisa também foi parcialmente apoiada pela concessão NIH AI120942 a S.C.W. e concede AI073755, AI104972 e AI106695 do NIH para M.S.D. P.F.C.V. foi suported por projetos de CAPES (Zika Fast-Track) e CNPq: bolsas 440405 / 2016-5 e 303999 / 2016-0 do Ministério da Ciência e Tecnologia de Brasil e pelo Ministério da Saúde.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA.University of Texas Medical Branch. Department of Microbiology & Immunology. Galveston, TX, USA.Washington University School of Medicine. Department of Medicine. St. Louis, MO, USA.Washington University School of Medicine. Department of Medicine. St. Louis, MO, USA.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Vaccine Research Center. Bethesda, MD, USA.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Vaccine Research Center. Bethesda, MD, USA.National Institutes of Health. National Institute of Allergy and Infectious Disease. Laboratory of Viral Diseases. Viral Pathogenesis Section. Bethesda, MD, USA.University of Texas Medical Branch. Institute for Human Infections & Immunity. Galveston, TX, USA / University of Texas Medical Branch. Department of Pathology. Galveston, TX, USA / University of Texas Medical Branch. Center for Biodefense & Emerging Infectious Diseases, , Galveston, TX, USA / University of Texas Medical Branch. Sealy Center for Vaccine Development. Galveston, TX, USA.University of Texas Medical Branch. Department of Microbiology & Immunology. Galveston, TX, USA / University of Texas Medical Branch. Sealy Center for Vaccine Development. Galveston, TX, USA / University of Texas Medical Branch. Institute for Translational Science. Galveston, TX, USA / University of Texas Medical Branch. Sealy Center for Structural Biology & Molecular Biophysics. Galveston, TX, USA.University of Texas Medical Branch. Institute for Human Infections & Immunity. Galveston, TX, USA / University of Texas Medical Branch. Department of Pathology. Galveston, TX, USA / University of Texas Medical Branch. Center for Biodefense & Emerging Infectious Diseases, , Galveston, TX, USA.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil / Pará State University. Department of Pathology. Belém, PA, Brazil.National Institutes of Health. National Institute of Allergy and Infectious Disease. Laboratory of Viral Diseases. Viral Pathogenesis Section. Bethesda, MD, USA.Washington University School of Medicine. Department of Medicine, , St. Louis, MO, USA / Washington University School of Medicine. Department of Molecular Microbiology. St. Louis, MO, USA / Washington University School of Medicine. Department of Pathology & Immunology. St. Louis, MO, USA / Washington University School of Medicine. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs. St. Louis, MO, USAUniversity of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / University of Texas Medical Branch. Sealy Center for Vaccine Development Galveston, TX, USA / University of Texas Medical Branch. Institute for Translational Science. Galveston, TX, USA / Pará State University. Department of Pathology. Belém, PA, Brazil / University of Texas Medical Branch. Department of Phamarcology & Toxicology. Galveston, TX, USA.Zika virus infection during pregnancy can cause congenital abnormities or fetal demise. The persistence of Zika virus in the male reproductive system poses a risk of sexual transmission. Here we demonstrate that live-attenuated Zika virus vaccine candidates containing deletions in the 3' untranslated region of the Zika virus genome (ZIKV-3'UTR-LAV) prevent viral transmission during pregnancy and testis damage in mice, as well as infection of nonhuman primates. After a single-dose vaccination, pregnant mice challenged with Zika virus at embryonic day 6 and evaluated at embryonic day 13 show markedly diminished levels of viral RNA in maternal, placental, and fetal tissues. Vaccinated male mice challenged with Zika virus were protected against testis infection, injury, and oligospermia. A single immunization of rhesus macaques elicited a rapid and robust antibody response, conferring complete protection upon challenge. Furthermore, the ZIKV-3'UTR-LAV vaccine candidates have a desirable safety profile. These results suggest that further development of ZIKV-3'UTR-LAV is warranted for humans.Zika virus infection can result in congenital disorders and cause disease in adults, and there is currently no approved vaccine. Here Shan et al. show that a single dose of a live-attenuated Zika vaccine prevents infection, testis damage and transmission to the fetus during pregnancy in different animal models

Vaccine mediated protection against Zika virus-induced congenital disease

Washington University School of Medicine. Department of Medicine. St. Louis, MO, USA.Washington University School of Medicine. Department of Medicine. St. Louis, MO, USA.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA.National Institutes of Health. Laboratory of Viral Diseases. Viral Pathogenesis Section. Bethesda, MD. USAWashington University School of Medicine. Department of Obstetrics and Gynecology. St. Louis, MO, USA.Moderna Venture. Valera LLC. Technology Square. Cambridge, MA, USA.Washington University School of Medicine. Department of Medicine. St. Louis, MO, USA.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / University of Texas Medical Branch. Department of Pathology. Galveston, TX, USA.National Institutes of Health. Laboratory of Viral Diseases. Viral Pathogenesis Section. Bethesda, MD, USA.University of Texas Medical Branch. Department of Pathology. Galveston, TX, USA.University of Texas Medical Branch. Department of Microbiology and Immunology. Galveston, TX, USA / University of Texas Medical Branch. Sealy Center for Vaccine Development. Galveston, TX, USA.University of Texas Medical Branch. Department of Pathology. Galveston, TX, USA / University of Texas Medical Branch. Sealy Center for Vaccine Development. Galveston, TX, USA.University of Texas Medical Branch. Department of Microbiology and Immunology. Galveston, TX, USA / University of Texas Medical Branch. Institute for Human infections and Immunity. Galveston, TX, USA / University of Texas Medical Branch. Sealy Center for Vaccine Development. Galveston, TX, USA.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil / Pará State University. Department of Pathology. Belém, PA, Brazil.University of Texas Medical Branch. Department of Pathology. Galveston, TX, USA / University of Texas Medical Branch. Institute for Human infections and Immunity. Galveston, TX, USA.Moderna Venture. Valera LLC. Technology Square. Cambridge, MA, USA.Washington University School of Medicine. Department of Obstetrics and Gynecology. St. Louis, MO, USA / Washington University School of Medicine. Department of Pathology and Immunology. St. Louis, MO, USA.National Institutes of Health. Laboratory of Viral Diseases. Viral Pathogenesis Section. Bethesda, MD, USA.University of Texas Medical Branch. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / University of Texas Medical Branch. Institute for Translational Science. Galveston, TX, USA / University of Texas Medical Branch. Institute for Human infections and Immunity. Galveston, TX, USA / University of Texas Medical Branch. Department of Pharmacology & Toxicology. Galveston, TX, USA / University of Texas Medical Branch. Sealy Center for Structural Biology & Molecular Biophysics. Galveston, TX, USA.Washington University School of Medicine. Department of Medicine. St. Louis, MO, USA / Washington University School of Medicine. Department of Pathology and Immunology. St. Louis, MO, USA / Washington University School of Medicine. Department of Molecular Microbiology. St. Louis, MO, USA / Washington University School of Medicine. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs. St. Louis, MO, USA.The emergence of Zika virus (ZIKV) and its association with congenital malformations has prompted the rapid development of vaccines. Although efficacy with multiple viral vaccine platforms has been established in animals, no study has addressed protection during pregnancy. We tested in mice two vaccine platforms, a lipid nanoparticle-encapsulated modified mRNA vaccine encoding ZIKV prM and E genes and a live-attenuated ZIKV strain encoding an NS1 protein without glycosylation, for their ability to protect against transmission to the fetus. Vaccinated dams challenged with a heterologous ZIKV strain at embryo day 6 (E6) and evaluated at E13 showed markedly diminished levels of viral RNA in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal demise. As modified mRNA and live-attenuated vaccine platforms can restrict in utero transmission of ZIKV in mice, their further development in humans to prevent congenital ZIKV syndrome is warranted

Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility. Findings In 2016, there were 27.08 million (95% uncertainty interval [UI] 24.30-30.30 million) new cases of TBI and 0.93 million (0.78-1.16 million) new cases of SCI, with age-standardised incidence rates of 369 (331-412) per 100 000 population for TBI and 13 (11-16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55.50 million (53.40-57.62 million) and of SCI was 27.04 million (24 .98-30 .15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8.4% (95% UI 7.7 to 9.2), whereas that of SCI did not change significantly (-0.2% [-2.1 to 2.7]). Age-standardised incidence rates increased by 3.6% (1.8 to 5.5) for TBI, but did not change significantly for SCI (-3.6% [-7.4 to 4.0]). TBI caused 8.1 million (95% UI 6. 0-10. 4 million) YLDs and SCI caused 9.5 million (6.7-12.4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82-141) per 100 000 for TBI and 130 (90-170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions. Interpretation TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe

Feasibility of reporting results of large randomised controlled trials to participants:experience from the Fluoxetine or Control under supervision (FOCUS) trial

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results

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. Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627. Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05). Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision. Funding: British Heart Foundation