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1.
JAMA Neurol ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31545353

RESUMO

Importance: The benefit of mechanical thrombectomy (MT) in patients with stroke presenting with mild deficits (National Institutes of Health Stroke Scale [NIHSS] score <6) owing to emergency large-vessel occlusion (ELVO) remains uncertain. Objective: To assess the outcomes of patients with mild-deficits ELVO (mELVO) treated with MT vs best medical management (bMM). Data Sources: We retrospectively pooled patients with mELVO during a 5-year period from 16 centers. A meta-analysis of studies reporting efficacy and safety outcomes with MT or bMM among patients with mELVO was also conducted. Data were analyzed between 2013 and 2017. Study Selection: We identified studies that enrolled patients with stroke (within 24 hours of symptom onset) with mELVO treated with MT or bMM. Main Outcomes and Measures: Efficacy outcomes included 3-month favorable functional outcome and 3-month functional independence that were defined as modified Rankin Scale scores of 0 to 1 and 0 to 2, respectively. Safety outcomes included 3-month mortality and symptomatic and asymptomatic intracranial hemorrhage (ICH). Results: We evaluated a total of 251 patients with mELVO who were treated with MT (n = 138; 65 women; mean age, 65.2 years; median NIHSS score, 4; interquartile range [IQR], 3-5) or bMM (n = 113; 51 women; mean age, 64.8; median NIHSS score, 3; interquartile range [IQR], 2-4). The rate of asymptomatic ICH was lower in bMM (4.6% vs 17.5%; P = .002), while the rate of 3-month FI (after imputation of missing follow-up evaluations) was lower in MT (77.4% vs 88.5%; P = .02). The 2 groups did not differ in any other efficacy or safety outcomes. In multivariable analyses, MT was associated with higher odds of asymptomatic ICH (odds ratio [OR], 11.07; 95% CI, 1.31-93.53; P = .03). In the meta-analysis of 4 studies (843 patients), MT was associated with higher odds of symptomatic ICH in unadjusted analyses (OR, 5.52; 95% CI, 1.91-15.49; P = .002; I2 = 0%). This association did not retain its significance in adjusted analyses including 2 studies (OR, 2.06; 95% CI, 0.49-8.63; P = .32; I2 = 0%). The meta-analysis did not document any other independent associations between treatment groups and safety or efficacy outcomes. Conclusions and Relevance: Our multicenter study coupled with the meta-analysis suggests similar outcomes of MT and bMM in patients with stroke with mELVO, but no conclusions about treatment effect can be made. The clinical equipoise can further be resolved by a randomized clinical trial.

3.
Ann Clin Transl Neurol ; 6(8): 1546-1551, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31402613

RESUMO

Prior studies suggest an association between Vitamin K antagonists (VKA) and cerebral microbleeds (CMBs); less is known about nonvitamin K oral anticoagulants (NOACs). In this observational study we describe CMB profiles in a multicenter cohort of 89 anticoagulation-related intracerebral hemorrhage (ICH) patients. CMB prevalence was 51% (52% in VKA-ICH, 48% in NOAC-ICH). NOAC-ICH patients had lower median CMB count [2(IQR:1-3) vs. 7(4-11); P < 0.001]; ≥5 CMBs were less prevalent in NOAC-ICH (4% vs. 31%, P = 0.006). This inverse association between NOAC exposure and high CMB count persisted in multivariable logistic regression models adjusting for potential confounders (OR 0.10, 95%CI: 0.01-0.83; P = 0.034).

4.
J Stroke Cerebrovasc Dis ; 28(9): 2448-2452, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31307898

RESUMO

BACKGROUND AND AIMS: Increasingly, insertable cardiac monitors (ICM) have been used to detect Atrial Fibrillation (AF) in patients with cryptogenic stroke or embolic strokes of undetermined source (ESUS). We aim to examine the characteristics of these patients who were subsequently found to have AF. METHODS: We studied 83 consecutive patients who were comprehensively evaluated using neuroimaging and vessel imaging (computed tomography angiography, magnetic resonance angiography, or transcranial and extracranial Doppler sonography) to have met the previously established ESUS criteria. All 83 patients had ICM implanted between 2015 and 2017. All patients were followed up for at least 1 year, with a median follow-up period of 1.5 ± .5 years. We compared the baseline clinical, laboratory, echocardiographic, neuro-imaging profiles, and clinical outcomes in terms of functional recovery, recurrent stroke, and mortality in patients with and without detected AF. RESULTS: AF detection rate in this ESUS cohort was 12% over the study period. Patients with detected AF were associated with bilateral infarcts pattern at presentation (30% versus 5.5%, P = .035). Infarcts involving multiple vascular territories was not significantly associated with the detection of AF. There were no significant differences in the other clinical characteristics and outcomes between the AF group compared to the group without detected AF. Echocardiographic parameters including left ventricular ejection fraction and left atrial diameter were also not shown to be significantly different. CONCLUSION: Our study found that a neuroimaging profile of bilateral infarcts was associated with AF detection using insertable cardiac monitor in ESUS patients. Larger prospective studies are needed to validate our findings.


Assuntos
Fibrilação Atrial/diagnóstico , Infarto Encefálico/epidemiologia , Frequência Cardíaca , Embolia Intracraniana/epidemiologia , Monitorização Ambulatorial/instrumentação , Telemetria/instrumentação , Idoso , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/mortalidade , Fibrilação Atrial/terapia , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/mortalidade , Infarto Encefálico/terapia , Feminino , Humanos , Incidência , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/mortalidade , Embolia Intracraniana/terapia , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Singapura/epidemiologia , Fatores de Tempo , Resultado do Tratamento
5.
JCI Insight ; 4(13)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31292297

RESUMO

Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell-mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.

6.
Br J Neurosurg ; : 1-2, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31347404

RESUMO

Background: Intracranial arterial stenosis is a common cause of ischemic stroke. Recent attempts with intracranial stenting and superficial temporal-middle cerebral artery (STA-MCA) bypass failed to show benefit. Perhaps, better strategies are needed for selecting suitable patients. Acetazolamide-challenged single photon emission computed tomography (SPECT) can demonstrate reversed Robin Hood syndrome (RRHS) due to intracranial steal phenomenon and identify high-risk patients. Methods: We describe the clinical and SPECT findings of RRHS. Results: In our patient with severe and symptomatic severe stenosis of the right MCA, STA-MCA bypass resulted in complete resolution of RRHS. Conclusion: STA-MCA bypass surgery should be considered a possible option in patients with severe stenosis of intracranial internal carotid artery or MCA in carefully selected patients.

7.
J Stroke Cerebrovasc Dis ; 28(8): 2332-2336, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31204203

RESUMO

BACKGROUND: Patients with initial transient ischaemic attack (TIA) subsequently have a higher risk of recurrent TIA or acute ischemic stroke (AIS). The role of scoring intracranial arterial calcification (IAC) in predicting the prevalence of stroke remains unclear. We aim to evaluate if radiological CT calcium score measuring IAC burden could predict future ischemic events in a cohort of TIA patients. METHODS: We studied consecutive patients from July 2014 to December 2015 who presented with first episode of TIA. All patients had noncontrasted CT or CT-angiogram of the brain on admission. CT calcium score (cm3) was quantified by measuring calcium deposition in the bilateral internal carotid arteries, middle cerebral arteries, and vertebrobasilar system. Patients were followed up for 2 years and ischemic events for either recurrent TIA or AIS were recorded. We compared patients in terms of clinical profile at presentation and CT calcium score using appropriate univariate and multivariable analyses. RESULTS: Of 156 TIA patients studied, 22% (n = 35) had recurrent TIA or AIS within 2 years of follow-up. On univariate analyses, recurrent TIA/AIS was associated with gender (OR 0.61; 95%CI 0.40-0.95; P = .038), hypertension (mean difference 2.49; 95%CI 1.08-5.75; P = .030) and higher CT calcium score (mean difference 0.84 95%CI 0.16-1.52 P = .016). On multivariable logistic regression, a higher CT calcium score was significantly associated with recurrent TIA/AIS (adjusted OR 1.25 95%CI 1.01-1.55 P = .042). CONCLUSIONS: In TIA patients, higher IAC burden by measurement of a quantitative CT calcium score may be associated with recurrent ischemic events.


Assuntos
Artérias/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Angiografia Cerebral/métodos , Doenças Arteriais Cerebrais/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Ataque Isquêmico Transitório/diagnóstico por imagem , Calcificação Vascular/diagnóstico por imagem , Adulto , Idoso , Artéria Basilar/diagnóstico por imagem , Artéria Carótida Interna/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Valor Preditivo dos Testes , Prognóstico , Recidiva , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Artéria Vertebral/diagnóstico por imagem
8.
Int J Stroke ; 14(7): 670-677, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31226919

RESUMO

OBJECTIVE: To investigate the comparative efficacy and safety of the low-dose versus standard-dose alteplase using real-world acute stroke registry data from Asian countries. METHODS: Individual participant data were obtained from nine acute stroke registries from China, Japan, Philippines, Singapore, South Korea, and Taiwan between 2005 and 2018. Inverse probability of treatment weight was used to remove baseline imbalances between those receiving low-dose versus standard-dose alteplase. The primary outcome was death or disability defined by modified Rankin Scale scores of 2 to 6 at 90 days. Secondary outcomes were symptomatic intracerebral hemorrhage and death. Generalized linear mixed models with the individual registry as a random intercept were performed to determine associations of treatment with low-dose alteplase and outcomes. RESULTS: Of the 6250 patients (mean age 66 years, 36% women) included in these analyses, 1610 (24%) were treated with low-dose intravenous alteplase. Clinical outcomes for low-dose alteplase were not significantly different to those for standard-dose alteplase, adjusted odds ratios for death or disability: 1.00 (0.85-1.19) and symptomatic intracerebral hemorrhage 0.87 (0.63-1.19), except for lower death with borderline significance, 0.77 (0.59-1.01). CONCLUSIONS: The present analyses of real-world Asian acute stroke registry data suggest that low-dose intravenous alteplase has overall comparable efficacy for functional recovery and greater potential safety in terms of reduced mortality, to standard-dose alteplase for the treatment of acute ischemic stroke.

9.
PLoS One ; 14(6): e0218507, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31216348

RESUMO

Bovine NK-lysins are cationic antimicrobial proteins found predominantly in the cytosolic granules of T lymphocytes and NK-cells. NK-lysin-derived peptides show antimicrobial activity against both Gram positive and Gram negative bacteria. Mature NK-lysin protein has six well-conserved cysteine residues. This study was performed to assess whether synthetic bovine NK-lysin-derived peptide (bNK2A) forms disulfide bonds and whether disulfide bonds were essential for bNK2A antimicrobial activity. Two 30-mer bNK2A peptides were synthesized: one with two original cysteines and an analog with cysteines substituted with two serines. Mass spectrometry revealed lack of disulfide bonds in original peptide while CD spectrophotometry showed both peptides have similar α-helical structures. Since both peptides were equally inhibitory to Histophilus somni, disulfide bonds appeared dispensable for synthetic bNK2A peptide antibacterial activity.

10.
Int J Stroke ; 14(7): 678-685, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30961463

RESUMO

BACKGROUND: Randomized controlled trials provide high-level evidence, but the necessity to include selected patients may limit the generalisability of their results. METHODS: Comparisons were made of baseline and outcome data between patients with acute ischemic stroke (AIS) recruited into the alteplase-dose arm of the international, multi-center, Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED) in the United Kingdom (UK), and alteplase-treated AIS patients registered in the UK Sentinel Stroke National Audit Programme (SSNAP) registry, over the study period June 2012 to October 2015. RESULTS: There were 770 AIS patients (41.2% female; mean age 72 years) included in ENCHANTED at sites in England and Wales, which was 19.5% of alteplase-treated AIS patients registered in the SSNAP registry. Trial participants were significantly older, had lower baseline neurological severity, less likely Asian, and had more premorbid symptoms, hypertension and atrial fibrillation. Although ENCHANTED participants had higher rates of symptomatic intracerebral hemorrhage than those in SSNAP, there were no differences in onset-to-treatment time, levels of disability (assessed by the modified Rankin scale) at hospital discharge, and mortality over 90 days between groups. CONCLUSIONS: Despite the high level of participation, equipoise over the dose of alteplase among UK clinician investigators favored the inclusion of older, frailer, milder AIS patients in the ENCHANTED trial. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov . Unique identifier: NCT01422616.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31027333

RESUMO

The burnout syndrome is characterized by emotional exhaustion, depersonalization, and reduced personal achievement. Uncertainty exists about the prevalence of burnout among medical and surgical residents. Associations between burnout and gender, age, specialty, and geographical location of training are unclear. In this meta-analysis, we aimed to quantitatively summarize the global prevalence rates of burnout among residents, by specialty and its contributing factors. We searched PubMed, PsycINFO, Embase, and Web of Science to identify studies that examined the prevalence of burnout among residents from various specialties and countries. The primary outcome assessed was the aggregate prevalence of burnout among all residents. The random effects model was used to calculate the aggregate prevalence, and heterogeneity was assessed by I2 statistic and Cochran's Q statistic. We also performed meta-regression and subgroup analysis. The aggregate prevalence of burnout was 51.0% (95% CI: 45.0-57.0%, I2 = 97%) in 22,778 residents. Meta-regression found that the mean age (ß = 0.34, 95% CI: 0.28-0.40, p < 0.001) and the proportion of males (ß = 0.4, 95% CI = 0.10-0.69, p = 0.009) were significant moderators. Subgroup analysis by specialty showed that radiology (77.16%, 95% CI: 5.99-99.45), neurology (71.93%, 95% CI: 65.78-77.39), and general surgery (58.39%, 95% CI: 45.72-70.04) were the top three specialties with the highest prevalence of burnout. In contrast, psychiatry (42.05%, 95% CI: 33.09-51.58), oncology (38.36%, 95% CI: 32.69-44.37), and family medicine (35.97%, 95% CI: 13.89-66.18) had the lowest prevalence of burnout. Subgroup analysis also found that the prevalence of burnout in several Asian countries was 57.18% (95% CI: 45.8-67.85); in several European countries it was 27.72% (95% CI: 17.4-41.11) and in North America it was 51.64% (46.96-56.28). Our findings suggest a high prevalence of burnout among medical and surgical residents. Older and male residents suffered more than their respective counterparts.


Assuntos
Esgotamento Profissional/epidemiologia , Internato e Residência , Humanos , Medicina , Prevalência
12.
Sci Rep ; 9(1): 6401, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31024031

RESUMO

Shiga toxin-producing Escherichia coli O157:H7 (O157) can cause mild to severe gastrointestinal disease in humans. Cattle are the primary reservoir for O157, which colonizes the intestinal tract without inducing any overt clinical symptoms. Parenteral vaccination can reduce O157 shedding in cattle after challenge and limit zoonotic transmission to humans, although the impact of vaccination and vaccine formulation on cellular and mucosal immune responses are undetermined. To better characterize the cattle immune response to O157 vaccination, cattle were vaccinated with either water-in-oil-adjuvanted, formalin-inactivated hha deletion mutant of Shiga toxin 2 negative (stx2-) O157 (Adj-Vac); non-adjuvanted (NoAdj-Vac); or non-vaccinated (NoAdj-NoVac) and peripheral T cell and mucosal antibody responses assessed. Cattle in Adj-Vac group had a higher percentage of O157-specific IFNγ producing CD4+ and γδ+ T cells in recall assays compared to the NoAdj-Vac group. Furthermore, O157-specific IgA levels detected in feces of the Adj-Vac group were significantly lower in NoAdj-Vac group. Extracts prepared only from Adj-Vac group feces blocked O157 adherence to epithelial cells. Taken together, these data suggest parenteral administration of adjuvanted, inactivated whole-cell vaccines for O157 can induce O157-specific cellular and mucosal immune responses that may be an important consideration for a successful vaccination scheme.

13.
BMC Genomics ; 20(1): 196, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849935

RESUMO

BACKGROUND: Escherichia coli O157:H7 (O157) has been linked to numerous foodborne disease outbreaks. The ability to rapidly sequence and analyze genomes is important for understanding epidemiology, virulence, survival, and evolution of outbreak strains. In the current study, we performed comparative genomics to determine structural and functional features of the genome of a foodborne O157 isolate NADC 6564 and infer its evolutionary relationship to other O157 strains. RESULTS: The chromosome of NADC 6564 contained 5466 kb compared to reference strains Sakai (5498 kb) and EDL933 (5547 kb) and shared 41 of its 43 Linear Conserved Blocks (LCB) with the reference strains. However, 18 of 41 LCB had inverse orientation in NADC 6564 compared to the reference strains. NADC 6564 shared 18 of 19 bacteriophages with reference strains except that the chromosomal positioning of some of the phages differed among these strains. The additional phage (P19) of NADC 6564 was located on a 39-kb insertion element (IE) encoding several hypothetical proteins, an integrase, transposases, transcriptional regulators, an adhesin, and a phosphoethanolamine transferase (PEA). The complete homologs of the 39-kb IE were found in E. coli PCN061 of porcine origin. The IE-encoded PEA showed low homology (32-33%) to four other PEA in NADC 6564 and PEA linked to mobilizable colistin resistance in E. coli but was highly homologous (95%) to a PEA of uropathogenic, avian pathogenic, and enteroaggregative E. coli. NADC 6564 showed slightly higher minimum inhibitory concentration of colistin compared to the reference strains. The 39-kb IE also contained dndBCDE and dptFGH operons encoding DNA S-modification and a restriction pathway, linked to oxidative stress tolerance and self-defense against foreign DNA, respectively. Evolutionary tree analysis grouped NADC 6564 with lineage I O157 strains. CONCLUSIONS: These results indicated that differential phage counts and different chromosomal positioning of many bacteriophages and genomic islands might have resulted in recombination events causing altered chromosomal organization in NADC 6564. Evolutionary analysis grouped NADC 6564 with lineage I strains and suggested its earlier divergence from these strains. The ability to perform S-DNA modification might affect tolerance of NADC 6564 to various stressors.


Assuntos
Escherichia coli O157/genética , Microbiologia de Alimentos , Genômica , Bacteriófagos/fisiologia , Cromossomos Bacterianos/genética , Elementos de DNA Transponíveis/genética , Escherichia coli O157/enzimologia , Escherichia coli O157/virologia , Evolução Molecular , Genoma Bacteriano/genética , Ilhas Genômicas/genética , Óperon/genética , Transferases (Outros Grupos de Fosfato Substituídos)/genética
14.
Lancet Neurol ; 18(4): 338-347, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30878103

RESUMO

BACKGROUND: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. METHODS: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. FINDINGS: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77-1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80-1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53). INTERPRETATION: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. FUNDING: Cerevast Therapeutics.

15.
Lancet ; 393(10174): 877-888, 2019 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-30739745

RESUMO

BACKGROUND: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. METHODS: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. FINDINGS: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. INTERPRETATION: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. FUNDING: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/administração & dosagem , Administração Intravenosa , Idoso , Austrália/epidemiologia , Pressão Sanguínea/fisiologia , Isquemia Encefálica/patologia , Brasil/epidemiologia , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Hemorragias Intracranianas/epidemiologia , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos Prospectivos , República da Coreia/epidemiologia , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento
16.
PLoS One ; 14(1): e0208724, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30615620

RESUMO

OBJECTIVES: Forest fires in South Asia lead to widespread haze, where many healthy individuals develop psychosomatic symptoms. We investigated the effects of haze exposure on cerebral hemodynamics and new symptoms. We hypothesised that vasoactive substances present in the haze, would lead to vasodilation of cerebral vasculature, thereby altering cerebral hemodynamics, which in turn may account for new psychosomatic symptoms. METHODS: Seventy-four healthy volunteers were recruited, and serial transcranial Doppler (TCD) ultrasonography was performed to record blood flow parameters of bilateral middle cerebral arteries (MCA). The first TCD was performed in an air-conditioned environment. It was repeated outdoors after the participants spent 30-minutes in the haze environment. The prevailing level of pollutant standards index (PSI) was recorded. Appropriate statistical analyses were performed to compare cerebral hemodynamics at baseline and after haze exposure in all participants. Subgroup analyses were then employed to compare the findings between symptomatic and asymptomatic participants. RESULTS: Study participants' median age was 30 years (IQR 26-34), and new psychosomatic symptoms were reported by 35 (47.3%). There was a modest but significant decrease in pulsatility index (PI) and resistivity index (RI) in the left MCA after haze exposure (PI: p = 0.026; RI: p = 0.021). When compared to baseline parameters, haze exposure resulted in significantly lower mean PI (p = 0.001) and RI (p = 0.001) in symptomatic patients, but this difference was not present in asymptomatic patients (PI: p = 0.919; RI: p = 0.970). CONCLUSION: Haze causes significant alterations in cerebral hemodynamics in susceptible individuals, probably responsible for various psychosomatic symptoms. The prognostic implications and health effects of haze require evaluation in a larger study.


Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Velocidade do Fluxo Sanguíneo/fisiologia , Hemodinâmica/fisiologia , Adulto , Ásia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Dióxido de Carbono/toxicidade , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Feminino , Voluntários Saudáveis , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Artéria Cerebral Média/fisiologia , Fluxo Pulsátil/efeitos dos fármacos , Fluxo Pulsátil/fisiologia , Ultrassonografia Doppler Transcraniana
17.
Transpl Int ; 32(5): 502-515, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30597643

RESUMO

We aimed to evaluate patient factors including nonadherence and viral infection and de novo donor-specific antibody (dnDSA) characteristics [total immunoglobulin G (IgG), C1q, IgG3, and IgG4] as predictors of renal allograft failure in a multicenter cohort with dnDSA. We performed a retrospective observational study of 113 kidney transplant recipients with dnDSA and stored sera for analysis. Predictors of death-censored allograft loss were assessed by Cox proportional modeling. Death-censored allograft survival was 77.0% (87/113) during a median follow-up of 2.2 (IQR 1.2-3.7) years after dnDSA detection. Predictors of allograft failure included medication nonadherence [HR 6.5 (95% CI 2.6-15.9)], prior viral infection requiring immunosuppression reduction [HR 5.3 (95% CI 2.1-13.5)], IgG3 positivity [HR 3.8 (95% CI 1.5, 9.3)], and time post-transplant (years) until donor-specific antibody (DSA) detection [HR 1.2 (95% CI 1.0, 1.3)]. In the 67 patients who were biopsied at dnDSA detection, chronic antibody-mediated rejection [HR 11.4 (95% CI 2.3, 56.0)] and mixed rejection [HR 7.4 (95% CI 2.2, 24.8)] were associated with allograft failure. We conclude that patient factors, including a history of viral infection requiring immunosuppression reduction or medication nonadherence, combined with DSA and histologic parameters must be considered to understand the risk of allograft failure in patients with dnDSA.

18.
J Stroke Cerebrovasc Dis ; 28(4): 906-919, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30612890

RESUMO

BACKGROUND: Blood pressure (BP) is an important determinant of functional outcome in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV-tPA). Current guidelines recommend a BP target of 185/110 mmHg before IV-tPA bolus and maintaining it at less than 180/105 mmHg for the first 24 hours. However, the effect of blood pressure on various outcome measures after systemic thrombolysis remains unclear. METHODS: Following a systematic search of Medline and EMBASE, all observational studies reporting effect of pretreatment BP on 90-day functional outcome as measured by the modified Rankin Scale (mRS) and/ or incidence of symptomatic intracranial hemorrhage (sICH) in AIS patients receiving thrombolytic therapy were included. RESULTS: Of 2181 studies screened, 26 studies, involving 38,937 subjects, met inclusion criteria. Higher prethrombolysis systolic BP was significantly-associated with poorer 90-day functional outcome (Mean difference 3.87 mmHg; 95% confidence interval [CI] 1.18-6.56) and increased incidence of sICH (Mean difference 5.31; 95% CI 2.22-8.40). When studies were stratified by different cut-offs for functional outcome (mRS 0-1 versus 0-2) and definitions of sICH used (Randomized controlled trials or SITS-MOST), there was no significant difference in mean difference between the subgroups. CONCLUSIONS: Our data showed that higher prethrombolysis SBP was associated with poorer outcomes in thrombolysed acute ischemic stroke patients. This may suggest that more aggressive lowering of BP below the current recommendations prior to thrombolysis could be beneficial. The effect of early BP trends after tPA infusion could not be evaluated due to limited available data. Ongoing randomized clinical trials, like ENCHANTED, may provide further insights into the current guidelines and optimal BP levels.


Assuntos
Pressão Sanguínea , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Avaliação da Deficiência , Humanos , Infusões Intravenosas , Estudos Observacionais como Assunto , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Ativador de Plasminogênio Tecidual/administração & dosagem , Resultado do Tratamento
20.
Front Microbiol ; 9: 2462, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386316

RESUMO

Powdery mildew (PM) is one of the most devastating and wide spread fungal diseases of rose, which seriously decrease its productivity and commercial value. In the present study, the endophytic fungal communities of two wild Rosa varieties (Rosa multiflora Thunb and R. multiflora var. carnea Redouté and Thory) with different PM susceptibilities were studied through Illumina MiSeq sequencer. A total of 14,000,424 raw reads were obtained from 60 samples, and 6,862,953 tags were produced after merging paired-end reads. 4462 distinct OTUs were generated at a 97% similarity level. It was found that only 34.2% of OTUs shared between two plant varieties. All of the OTUs were assigned into four fungal phyla, 17 classes, 43 orders, 86 families, 157 genera, and 208 species. Members of Ascomycota were found to be the most common fungal endophytes (EF) among all plant samples (93.7% relative abundance), followed by Basidiomycota (4.7% relative abundance), while Zygomycota and Glomeromycota were found to be rare and incidental. At each developmental stage of plants, the diversity and community structure of EF between two Rosa varieties showed significant differences. Both PCoA plots and PERMANOVA analyses indicated that developmental stage was the major factor contributing to the difference between the Rosa varieties (R 2 = 0.348, p < 0.001). In addition, plant varieties and tissues were also important factors contributing to the difference (R 2 = 0.031, p < 0.05; R 2 = 0.029, p < 0.05). Moreover, Neofusicoccum, Rhodosporidium, and Podosphaera, etc., were found to be significantly different between two Rosa varieties, and some of the endophytes may play a role in PM resistance. These finding are encouraging to testify the potential use of these fungi in the biocontrol of PM in future studies.

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