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1.
Crit Care ; 26(1): 180, 2022 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-35710578

RESUMO

BACKGROUND: Andexanet alfa is approved (FDA "accelerated approval"; EMA "conditional approval") as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH). METHODS: This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression. RESULTS: The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16-6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13-0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC. CONCLUSIONS: In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.


Assuntos
Hemostáticos , Trombose , Adulto , Idoso , Anticoagulantes , Fatores de Coagulação Sanguínea/farmacologia , Fatores de Coagulação Sanguínea/uso terapêutico , Fator Xa/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Hemorragia , Humanos , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/tratamento farmacológico , Pontuação de Propensão , Estudos Prospectivos , Pirazóis , Piridonas , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Rivaroxabana/efeitos adversos
2.
J Stroke Cerebrovasc Dis ; 31(5): 106404, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35292423

RESUMO

BACKGROUND: The effect of interventions on functional impairment is an important outcome in stroke prevention trials and should be considered as an adjunct to counting discrete events. In the NAVIGATE-ESUS trial, 7213 patients with recent embolic strokes of undetermined source were randomized to rivaroxaban (15 mg once daily) or aspirin (100 mg daily). After 11 months there was no effect on the prevention of recurrent stroke. AIMS: To determine the effect of rivaroxaban compared to aspirin on functional and cognitive outcomes. METHODS: Function and cognition were measured at baseline, 1 year, and study end using the Standard Assessment of Global Everyday Activities (SAGEA), a 15-item scale assessing cognitive, instrumental, and basic activities of daily living as well as mobility, and the Montreal Cognitive Assessment (MoCA). Changes in scores were calculated by subtracting either study end or 1-year scores from baseline, and differences in distributions were compared using the Mann-Whitney U test. SAGEA and MoCA scores were also correlated with recurrent stroke. RESULTS: Follow-up SAGEA scores were available in 6378 (88%) participants. There was no difference in change in function for those allocated to rivaroxaban compared to aspirin (Mann-Whitney U test, p = 0.8), with both distributions having a median (25p,75p) change of 0 (-2,1). Overall, more of those who experienced a recurrent stroke (n=247; mostly minor ischemic), reported functional difficulty at study end versus entry, compared with those who did not (51% versus 30%, chi-square test, p< 0.001), and this was consistent across global regions. There was no difference in the change in cognition by treatment group, nor were recurrent strokes associated with a change in cognition. CONCLUSIONS: Rivaroxaban, compared to aspirin, was not associated with changes in functional or cognitive status in patients with recent ESUS. The SAGEA scale detected changes in functional status associated with recurrent strokes in an international stroke population.


Assuntos
AVC Embólico , Embolia Intracraniana , Acidente Vascular Cerebral , Atividades Cotidianas , Aspirina/efeitos adversos , Cognição , Método Duplo-Cego , Inibidores do Fator Xa/efeitos adversos , Humanos , Embolia Intracraniana/diagnóstico , Embolia Intracraniana/tratamento farmacológico , Embolia Intracraniana/etiologia , Inibidores da Agregação Plaquetária , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia
3.
Neurology ; 98(19): e1942-e1952, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35264426

RESUMO

BACKGROUND AND OBJECTIVES: Prolonged poststroke cardiac rhythm monitoring (PCM) reveals a substantial proportion of patients with ischemic stroke (IS) with atrial fibrillation (AF) not detected by conventional rhythm monitoring strategies. We evaluated the association between PCM and the institution of stroke preventive strategies and stroke recurrence. METHODS: We searched MEDLINE and SCOPUS databases to identify studies reporting stroke recurrence rates in patients with history of recent IS or TIA receiving PCM compared with patients receiving conventional cardiac rhythm monitoring. Pairwise meta-analyses were performed under the random effects model. To explore for differences between the monitoring strategies, we combined direct and indirect evidence for any given pair of monitoring devices assessed within a randomized controlled trial (RCT). RESULTS: We included 8 studies (5 RCTs, 3 observational; 2,994 patients). Patients receiving PCM after their index event had a higher rate of AF detection and anticoagulant initiation in RCTs (risk ratio [RR] 3.91, 95% CI 2.54-6.03; RR 2.16, 95% CI 1.66-2.80, respectively) and observational studies (RR 2.06, 95% CI 1.57-2.70; RR 2.01, 95% CI 1.43-2.83, respectively). PCM was associated with a lower risk of recurrent stroke during follow-up in observational studies (RR 0.29, 95% CI 0.15-0.59), but not in RCTs (RR 0.72, 95% CI 0.49-1.07). In indirect analyses of RCTs, the likelihood of AF detection and anticoagulation initiation was higher for implantable loop recorders compared with Holter monitors and external loop recorders. DISCUSSION: PCM after an IS or TIA can lead to higher rates of AF detection and anticoagulant initiation. There is no solid RCT evidence supporting that PCM may be associated with lower stroke recurrence risk.


Assuntos
Fibrilação Atrial , Ataque Isquêmico Transitório , AVC Isquêmico , Acidente Vascular Cerebral , Anticoagulantes , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Humanos , Ataque Isquêmico Transitório/complicações , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Acidente Vascular Cerebral/complicações
5.
Artigo em Inglês | MEDLINE | ID: mdl-35021968

RESUMO

TlyA proteins are related to distinct functions in a diverse spectrum of bacterial pathogens including mycobacterial spp. There are several annotated proteins function as hemolysin or pore forming molecules that play an important role in the virulence of pathogenic organisms. Many studies reported the dual activity of mycobacterial TlyA as 'hemolysin' and 'S-adenosylmethionine dependent rRNA methylase'. To act as a hemolysin, a sequence must have a signal sequence and transmembrane segment which helps the protein to enter the extracellular environment. Interestingly, the mycobacterial tlyA has neither a traditional signal sequences of general/sec/tat pathways nor any transmembrane segments are present. Still it can reach the extracellular milieu with the help of non-classical signal mechanisms. Also, retention of tlyA in cultivable mycobacterial pathogens (such as Mycobacterium tuberculosis and M. marinum) as well as uncultivated mycobacterial pathogens despite their extreme reductive evolution (such as M. leprae, M. lepromatosis and M. uberis) suggests its crucial role in evolutionary biology of pathogenic mycobacteria. Numerous virulence factors have been characterised from the uncultivable mycobacteria but the information of TlyA protein is still limited in terms of molecular and structural characterisation. The genomic insights offered by comparative analysis of TlyA sequences and its conserved domains reveal its pore forming activity which further confirms its role as a virulence protein, particularly in uncultivable mycobacteria. Therefore, this review presents a comparative analysis of mycobacterial TlyA family by sequence homology and alignment to improve our understanding of this unconventional hemolysin and RNA methyltransferase TlyA of uncultivable mycobacteria.

7.
Stroke ; 53(1): 45-52, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34538089

RESUMO

BACKGROUND AND PURPOSE: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial. METHODS: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics. RESULTS: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26-115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack (P<0.001), modified Rankin Scale score >0 (P<0.001), and current tobacco use (P=0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS. CONCLUSIONS: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02313909.


Assuntos
Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/tratamento farmacológico , Rivaroxabana/uso terapêutico , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Estudos de Coortes , Método Duplo-Cego , Feminino , Humanos , Internacionalidade , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico
9.
Int J Stroke ; : 17474930211058012, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34791941

RESUMO

BACKGROUND: Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown. AIMS: To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies. METHODS: At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression. RESULTS: Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52-1.7). CONCLUSIONS: Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide.Registration: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

10.
Artigo em Inglês | MEDLINE | ID: mdl-34620073

RESUMO

Leprosy is caused by extremely slow-growing and uncultivated mycobacterial pathogens, namely Mycobacterium leprae and M. lepromatosis. Nearly 95% of the new cases of leprosy recorded globally are found in India, Brazil, and 20 other priority countries [WHO, 2019], of which nearly two-thirds of the cases are reported in India alone. Currently, leprosy is treated with dapsone, rifampicin, and clofazimine, also known as multi-drug therapy [MDT], as per the recommendations of WHO since 1981. Still, the number of new leprosy cases recorded globally has remained constant in the last one-decade ,and resistance to multiple drugs has been documented in various parts of the world, even though relapses are rare in patients treated with MDT. Antimicrobial resistance testing against M. leprae or the evaluation of the anti-leprosy activity of new drugs remains a challenge as leprosy bacilli do not grow in vitro. Besides, developing a new drug against leprosy through the conventional drug development process is not economically attractive or viable for pharma companies. Therefore, a promising alternative is the repurposing of existing drugs/approved medications or their derivatives for assessing their anti-leprosy potential. It is an efficient method to identify novel medicinal and therapeutic properties of approved drug molecules. Any combinatorial chemotherapy that combines these repurposed drugs with the existing first-line [MDT] and second-line drugs could improve the bactericidal and synergistic effects against these notorious bacteria and can help in achieving the much-cherished goal of "leprosy-free world". This review highlights novel opportunities for drug repurposing to combat resistance to current therapeutic approaches.

11.
J Dermatol ; 48(12): 1936-1939, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34676580

RESUMO

We have developed a polymerase chain reaction-based method to detect and distinguish Mycobacterium leprae and Mycobacterium lepromatosis using a single set of primers based on a 45-bp difference in the amplicon size of their rpoT gene. This method can also help in detecting the cases of co-infection in a single experiment.


Assuntos
Hanseníase , Mycobacterium , Humanos , Hanseníase/diagnóstico , Mycobacterium/genética , Mycobacterium leprae/genética , Reação em Cadeia da Polimerase
12.
CJEM ; 23(6): 812-819, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34468970

RESUMO

BACKGROUND: Transient ischemic attack (TIA) and non-disabling stroke are common emergency department (ED) presentations. Currently, there are no prospective multicenter studies determining predictors of neurologists confirming a diagnosis of cerebral ischemia in patients discharged with a diagnosis of TIA or stroke. The objectives were to (1) calculate the concordance between emergency physicians and neurologists for the outcome of diagnosing TIA or stroke, and (2) identify characteristics associated with neurologists diagnosing a stroke mimic. METHODS: This was a planned sub-study of a prospective cohort study at 14 Canadian EDs enrolling patients diagnosed with TIA or non-disabling stroke from 2006 to 2017. Logistic regression was used to identify factors associated with neurologists' diagnosis of cerebral ischemia. Our primary outcome was the composite outcome of cerebral ischemia (TIA or non-disabling stroke) based on the neurologists' assessment. RESULTS: The diagnosis of cerebral ischemia was confirmed by neurologists in 5794 patients (55.4%). The most common identified stroke mimics were migraine (18%), peripheral vertigo (7%), syncope (4%), and seizure (3%). Over a third of patients (38.4%) ultimately had an undetermined aetiology for their symptoms. The strongest predictors of cerebral ischemia confirmation were infarct on CT (OR 1.83, 95% CI 1.65-2.02), advanced age (OR comparing 75th-25th percentiles 1.67, 1.55-1.80), language disturbance (OR 1.92, 1.75-2.10), and smoking (OR 1.67, 1.46-1.91). The strongest predictors of stroke mimics were syncope (OR 0.59, 0.48-0.72), vertigo (OR 0.52, 0.45-0.59), bilateral symptoms (OR 0.60, 0.50-0.72), and confusion (OR 0.50, 0.44-0.57). CONCLUSION: Physicians should have a high index of suspicion of cerebral ischemia in patients with advanced age, smoking history, language disturbance, or infarcts on CT. Physicians should discriminate in which patients to pursue stroke investigations on when deemed at minimal risk of cerebral ischemia, including those with isolated vertigo, syncope, or bilateral symptoms.


RéSUMé: CONTEXTE: L'accident ischémique transitoire (AIT) et l'accident vasculaire cérébral (AVC) non invalidant sont des présentations courantes dans les services d'urgence. Actuellement, il n'existe pas d'études prospectives multicentriques déterminant les facteurs prédictifs de la confirmation par les neurologues d'un diagnostic d'ischémie cérébrale chez les patients sortis de l'hôpital avec un diagnostic d'AIT ou d'AVC. Les objectifs étaient de (1) calculer la concordance entre les urgentistes et les neurologues pour le résultat du diagnostic de l'AIT ou de l'AVC, et (2) identifier les caractéristiques associées au diagnostic par les neurologues d'une imitation d'AVC. MéTHODES: Il s'agissait d'une sous-étude planifiée d'une étude de cohorte prospective dans 14 services d'urgence canadiens recrutant des patients diagnostiqués avec un AIT ou un AVC non invalidant de 2006 à 2017. Une régression logistique a été utilisée pour identifier les facteurs associés au diagnostic d'ischémie cérébrale par les neurologues. Notre résultat principal était le résultat composite de l'ischémie cérébrale (AIT ou accident vasculaire cérébral non invalidant) selon l'évaluation des neurologues. RéSULTATS: Le diagnostic d'ischémie cérébrale a été confirmé par des neurologues chez 5 794 patients (55,4 %). Les imitateurs d'AVC identifiés les plus courants étaient la migraine (18 %), le vertige périphérique (7 %), la syncope (4 %) et les convulsions (3 %). Plus d'un tiers des patients (38,4 %) avaient finalement une étiologie indéterminée pour leurs symptômes. Les prédicteurs les plus forts de la confirmation de l'ischémie cérébrale étaient l'infarctus au scanner (OR 1.83, IC 95 % 1.65­2.02), l'âge avancé (OR comparant les 75e et 25e percentiles 1.67, 1.55­1.80), les troubles du langage (OR 1.92, 1.75­2.10) et le tabagisme (OR 1.67, 1.46­1.91). Les prédicteurs les plus forts d'imitateurs d'AVC étaient la syncope (OR 0.59, 0.48­0.72), le vertige (OR 0.52, 0.45­0.59), les symptômes bilatéraux (OR 0.60, 0.50­0.72) et la confusion (OR 0.50, 0.44­0.57). CONCLUSION: Les médecins devraient avoir un indice élevé de suspicion d'ischémie cérébrale chez les patients ayant un âge avancé, des antécédents de tabagisme, des troubles du langage ou des infarctus au scanner. Les médecins doivent distinguer les patients sur lesquels poursuivre des investigations sur un AVC lorsqu'ils sont jugés à risque minimal d'ischémie cérébrale, y compris ceux présentant des vertiges isolés, une syncope ou des symptômes bilatéraux.


Assuntos
Ataque Isquêmico Transitório , Médicos , Canadá/epidemiologia , Serviço Hospitalar de Emergência , Humanos , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/epidemiologia , Neurologistas , Estudos Prospectivos , Fatores de Risco
14.
J Am Coll Cardiol ; 78(1): 14-23, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34210409

RESUMO

BACKGROUND: The combination of 2.5 mg rivaroxaban twice daily and 100 mg aspirin once daily compared with 100 mg aspirin once daily reduces major adverse cardiovascular (CV) events in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD). OBJECTIVES: The aim of this work was to report the effects of the combination on overall and cause-specific mortality. METHODS: The COMPASS trial enrolled 27,395 patients of whom 18,278 were randomized to the combination (n = 9,152) or aspirin alone (n = 9,126). Deaths were adjudicated by a committee blinded to treatment allocation. Previously identified high-risk baseline features were polyvascular disease, chronic kidney disease, mild or moderate heart failure, and diabetes. RESULTS: During a median of 23 months of follow-up (maximum 47 months), 313 patients (3.4%) allocated to the combination and 378 patients (4.1%) allocated to aspirin alone died (hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.71-0.96; P = 0.01). Compared with aspirin, the combination reduced CV death (160 [1.7%] vs 203 [2.2%]; HR: 0.78; 95% CI: 0.64-0.96; P = 0.02) but not non-CV death. There were fewer deaths following MI, stroke, and CV procedures, as well as fewer sudden cardiac, other, and unknown causes of CV deaths and coronary heart disease deaths. Patients with 0, 1, 2, and 3 or 4 high-risk features at baseline had 4.2, 4.8, 25.0, and 53.9 fewer deaths, respectively, per 1000 patients treated for 30 months. CONCLUSIONS: The combination of rivaroxaban and aspirin compared with aspirin reduced overall and CV mortality with consistent reductions in cause specific CV mortality in patients with chronic CAD or PAD. The absolute mortality benefits are greater with increasing baseline risk. (Cardiovascular Outcomes for People Using Anticoagulant Strategies [COMPASS]; NCT01776424).


Assuntos
Aspirina , Doença da Artéria Coronariana , Doença Arterial Periférica , Rivaroxabana , Idoso , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/mortalidade , Diabetes Mellitus/epidemiologia , Quimioterapia Combinada , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/mortalidade , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Medição de Risco , Fatores de Risco , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Índice de Gravidade de Doença
15.
Infect Genet Evol ; 94: 105015, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34311096

RESUMO

The genome of a newly identified leprosy causing bacillus Mycobacterium lepromatosis was sequenced in 2015 wherein a gene MLPM_5000 was detected whose corresponding sequences are missing in its close relative Mycobacterium leprae, the well-known causal agent of leprosy. Thus MLPM_5000 is considered to be a specific genomic locus for differentiating M. lepromatosis from M. leprae. The locus was annotated as HemN (Coproporphyrinogen III oxidase) based on the available annotations in other mycobacterial species. However, we noticed that the MLPM_5000 and its orthologues in different mycobacterial species show a much higher degree of similarity with Escherichia coli HemW (378 aa) in comparison to the E. coli HemN (457 aa). Additionally, the fourth cysteine of the characteristic CX3CX2CXC motif of the E. coli HemN is replaced by a phenylalanine in the M. lepromatosis MLPM_5000 and its mycobacterial orthologues, which is a hallmark of heme chaperone protein HemW in E. coli and other species. Phylogenetic analysis of MLPM_5000 and its mycobacterial orthologues also showed that these proteins form a divergent phylogenetic clade with the HemW proteins of other species such as Escherichia coli and Lactococcus lactis. Further, Molecular Dynamics simulation studies also predicted that the residues of conserved HNXXYW motif of the MLPM_5000 may have a role in binding to heme part of the host hemoglobin, thereby suggesting it to be a HemW instead of HemN. Altogether, this work shows that MLPM_5000 and its mycobacterial orthologues are highly unlikely to be HemN. Therefore, the current annotations of mycobacterial HemN sequences should be corrected to heme chaperone 'HemW' in various protein databases. The study not only corrects the mis-annotation but also provides a new perspective in the context of evolutionary history of M. leprae and M. lepromatosis such as lack of HemW in M. leprae may explain some of the variations in the virulence between the two pathogens.


Assuntos
Proteínas de Bactérias/genética , Hemeproteínas/genética , Anotação de Sequência Molecular , Mycobacterium/genética , Hanseníase/microbiologia
16.
N Engl J Med ; 384(22): 2081-2091, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33999547

RESUMO

BACKGROUND: Surgical occlusion of the left atrial appendage has been hypothesized to prevent ischemic stroke in patients with atrial fibrillation, but this has not been proved. The procedure can be performed during cardiac surgery undertaken for other reasons. METHODS: We conducted a multicenter, randomized trial involving participants with atrial fibrillation and a CHA2DS2-VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating greater risk of stroke) who were scheduled to undergo cardiac surgery for another indication. The participants were randomly assigned to undergo or not undergo occlusion of the left atrial appendage during surgery; all the participants were expected to receive usual care, including oral anticoagulation, during follow-up. The primary outcome was the occurrence of ischemic stroke (including transient ischemic attack with positive neuroimaging) or systemic embolism. The participants, research personnel, and primary care physicians (other than the surgeons) were unaware of the trial-group assignments. RESULTS: The primary analysis population included 2379 participants in the occlusion group and 2391 in the no-occlusion group, with a mean age of 71 years and a mean CHA2DS2-VASc score of 4.2. The participants were followed for a mean of 3.8 years. A total of 92.1% of the participants received the assigned procedure, and at 3 years, 76.8% of the participants continued to receive oral anticoagulation. Stroke or systemic embolism occurred in 114 participants (4.8%) in the occlusion group and in 168 (7.0%) in the no-occlusion group (hazard ratio, 0.67; 95% confidence interval, 0.53 to 0.85; P = 0.001). The incidence of perioperative bleeding, heart failure, or death did not differ significantly between the trial groups. CONCLUSIONS: Among participants with atrial fibrillation who had undergone cardiac surgery, most of whom continued to receive ongoing antithrombotic therapy, the risk of ischemic stroke or systemic embolism was lower with concomitant left atrial appendage occlusion performed during the surgery than without it. (Funded by the Canadian Institutes of Health Research and others; LAAOS III ClinicalTrials.gov number, NCT01561651.).


Assuntos
Apêndice Atrial/cirurgia , Fibrilação Atrial/cirurgia , Embolia/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Idoso , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Procedimentos Cirúrgicos Cardíacos , Terapia Combinada , Embolia/epidemiologia , Feminino , Humanos , Complicações Intraoperatórias/epidemiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/epidemiologia
17.
BMJ ; 372: n49, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541890

RESUMO

OBJECTIVE: To validate the previously derived Canadian TIA Score to stratify subsequent stroke risk in a new cohort of emergency department patients with transient ischaemic attack. DESIGN: Prospective cohort study. SETTING: 13 Canadian emergency departments over five years. PARTICIPANTS: 7607 consecutively enrolled adult patients attending the emergency department with transient ischaemic attack or minor stroke. MAIN OUTCOME MEASURES: The primary outcome was subsequent stroke or carotid endarterectomy/carotid artery stenting within seven days. The secondary outcome was subsequent stroke within seven days (with or without carotid endarterectomy/carotid artery stenting). Telephone follow-up used the validated Questionnaire for Verifying Stroke Free Status at seven and 90 days. All outcomes were adjudicated by panels of three stroke experts, blinded to the index emergency department visit. RESULTS: Of the 7607 patients, 108 (1.4%) had a subsequent stroke within seven days, 83 (1.1%) had carotid endarterectomy/carotid artery stenting within seven days, and nine had both. The Canadian TIA Score stratified the risk of stroke, carotid endarterectomy/carotid artery stenting, or both within seven days as low (risk ≤0.5%; interval likelihood ratio 0.20, 95% confidence interval 0.09 to 0.44), medium (risk 2.3%; interval likelihood ratio 0.94, 0.85 to 1.04), and high (risk 5.9% interval likelihood ratio 2.56, 2.02 to 3.25) more accurately (area under the curve 0.70, 95% confidence interval 0.66 to 0.73) than did the ABCD2 (0.60, 0.55 to 0.64) or ABCD2i (0.64, 0.59 to 0.68). Results were similar for subsequent stroke regardless of carotid endarterectomy/carotid artery stenting within seven days. CONCLUSION: The Canadian TIA Score stratifies patients' seven day risk for stroke, with or without carotid endarterectomy/carotid artery stenting, and is now ready for clinical use. Incorporating this validated risk estimate into management plans should improve early decision making at the index emergency visit regarding benefits of hospital admission, timing of investigations, and prioritisation of specialist referral.


Assuntos
Ataque Isquêmico Transitório/diagnóstico , Medição de Risco/métodos , Acidente Vascular Cerebral/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Canadá , Comorbidade , Serviço Hospitalar de Emergência/estatística & dados numéricos , Endarterectomia das Carótidas/estatística & dados numéricos , Feminino , Humanos , Ataque Isquêmico Transitório/epidemiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos
18.
J Med Biochem ; 40(1): 92-98, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33584145

RESUMO

BACKGROUND: Kit lot change in clinical biochemistry labs leads to variations in patient results. This study planned to identify variations during 60 reagent lot changes in our laboratory during the period from June 2018 to May 2019. METHODS: A statistical analysis was performed to identify the difference between patient samples results variations and QC results. The long term drift was analyzed using a regression test. RESULTS: There was a significant difference between the patient and QC results in 16.7% of reagent lot changes. Moreover, the extent of variation in QC results was 3.3%. No long-term drift was seen in three analytes which were studied using regression analysis. CONCLUSIONS: Our results showed that, during reagent kit lot change, along with QC material, the patient samples should also be run in order to identify the variation. However, this practice is presently ignored by most of the laboratories. There was no accumulated effect in our laboratory due to reagent kit lot change.

19.
JAMA Neurol ; 78(1): 11-20, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33074284

RESUMO

Importance: The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging. Objective: To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy. Design, Setting, and Participants: Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial. Interventions: Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily. Main Outcomes and Measures: The primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality. Results: Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI, 1.54-3.15), multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97). Conclusions and Relevance: Microbleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.


Assuntos
Anticoagulantes/uso terapêutico , Hemorragia Cerebral/etiologia , AVC Embólico/complicações , AVC Embólico/tratamento farmacológico , Idoso , Aspirina/uso terapêutico , Hemorragia Cerebral/epidemiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Recidiva , Rivaroxabana/uso terapêutico
20.
Can J Neurol Sci ; 48(1): 59-65, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32741386

RESUMO

BACKGROUND: We investigated the impact of regionally imposed social and healthcare restrictions due to coronavirus disease 2019 (COVID-19) to the time metrics in the management of acute ischemic stroke patients admitted at the regional stroke referral site for Central South Ontario, Canada. METHODS: We compared relevant time metrics between patients with acute ischemic stroke receiving intravenous tissue plasminogen activator (tPA) and/or endovascular thrombectomy (EVT) before and after the declared restrictions and state of emergency imposed in our region (March 17, 2020). RESULTS: We identified a significant increase in the median door-to-CT times for patients receiving intravenous tPA (19 min, interquartile range (IQR): 14-27 min vs. 13 min, IQR: 9-17 min, p = 0.008) and/or EVT (20 min, IQR: 15-33 min vs. 11 min, IQR: 5-20 min, p = 0.035) after the start of social and healthcare restrictions in our region compared to the previous 12 months. For patients receiving intravenous tPA treatment, we also found a significant increase (p = 0.005) in the median door-to-needle time (61 min, IQR: 46-72 min vs. 37 min, IQR: 30-50 min). No delays in the time from symptom onset to hospital presentation were uncovered for patients receiving tPA and/or endovascular reperfusion treatments in the first 1.5 months after the establishment of regional and institutional restrictions due to the COVID-19 pandemic. CONCLUSION: We detected an increase in our institutional time to treatment metrics for acute ischemic stroke patients receiving tPA and/or endovascular reperfusion therapies, related to delays from hospital presentation to the acquisition of cranial CT imaging for both tPA- and EVT-treated patients, and an added delay to treatment with tPA.


Délais dans le traitement en milieu hospitalier des AVC aigus dans le contexte de la pandémie de COVID-19. CONTEXTE: Nous nous sommes penchés, dans le contexte de la pandémie de COVID-19, sur l'impact de restrictions régionales imposées dans le domaine social et dans les soins de santé sur les délais de prise en charge de patients victimes d'un AVC aigu. À noter que ces patients ont été admis dans un centre régional de traitement des AVC situé dans le centre-ouest de l'Ontario (Canada). MÉTHODES: Nous avons comparé entre eux les délais de prise en charge de patients ayant bénéficié d'activateurs tissulaires du plasminogène par intraveineuse (tPA) et/ou d'une procédure de thrombectomie endovasculaire (TE) avant et après la mise sur pied de restrictions et l'imposition d'un état d'urgence sanitaire dans notre région (17 mars 2020). RÉSULTATS: Après la mise sur pied de ces restrictions, nous avons identifié, par rapport aux 12 mois précédent, une augmentation notable des délais médians entre l'arrivée à l'hôpital et un examen de tomodensitométrie dans le cas de patients bénéficiant de tPA (19 minutes, EI : 14­27 minutes contre 13 minutes, EI : 9­17 minutes ; p = 0,008) et/ou d'une procédure de TE (20 minutes, EI : 15­33 minutes contre 11 minutes, EI : 5­20 minutes ; p = 0,035). Pour ce qui est des patients bénéficiant de tPA, nous avons également observé une augmentation importante (p = 0,005) des délais médians entre leur arrivée à l'hôpital et l'injection d'un traitement (61 minutes, EI : 46­72 minutes contre 37 minutes, EI : 30­50 minutes). Enfin, dans le premier mois et demi suivant la mise sur pied des restrictions régionales et institutionnelles attribuables à la pandémie de COVID-19, aucun délai supplémentaire entre l'apparition des premiers symptômes d'un AVC et l'arrivée à l'hôpital n'a été remarqué pour des patients bénéficiant de tPA et/ou d'une procédure de TE. CONCLUSION: En somme, nous avons détecté une augmentation de nos délais de traitement dans le cas de patients victimes d'un AVC aigu ayant bénéficié de tPA et/ou d'une procédure de TE. Cela peut être attribué à une augmentation des délais de présentation à l'hôpital mais aussi à des délais dans l'obtention d'images de tomodensitométrie pour des patients traités avec des tPA et une procédure de TE, sans compter des délais accrus pour bénéficier d'un traitement de tPA.


Assuntos
Procedimentos Endovasculares/estatística & dados numéricos , AVC Isquêmico/terapia , Trombectomia/estatística & dados numéricos , Terapia Trombolítica/estatística & dados numéricos , Tempo para o Tratamento/tendências , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Atenção à Saúde/tendências , Feminino , Fibrinolíticos/uso terapêutico , Humanos , AVC Isquêmico/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Ontário , SARS-CoV-2 , Ativador de Plasminogênio Tecidual/uso terapêutico , Tomografia Computadorizada por Raios X/estatística & dados numéricos
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