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1.
Small ; 20(28): e2311448, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38326094

RESUMO

The development of a cost-effective, ultra-selective, and room temperature gas sensor is the need of an hour, owing to the rapid industrialization. Here, a new 2D semiconducting Cu(I) coordination polymer (CP) with 1,4-di(1H-1,2,4-triazol-1-yl)benzene (1,4-TzB) ligand is reported. The CP1 consists of a Cu2I2 secondary building unit bridged by 1,4-TzB, and has high stability as well as semiconducting properties. The chemiresistive sensor, developed by a facile drop-casting method derived from CP1, demonstrates a response value of 66.7 at 100 ppm on methanol exposure, accompanied by swift transient (response and recovery time 17.5 and 34.2 s, respectively) behavior. In addition, the developed sensor displays ultra-high selectivity toward methanol over other volatile organic compounds , boasting LOD and LOQ values of 1.22 and 4.02 ppb, respectively. The CP is found to be a state-of-the-art chemiresistive sensor with ultra-high sensitivity and selectivity toward methanol at room temperature.

2.
J Neurointerv Surg ; 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38171611

RESUMO

BACKGROUND: Mechanical thrombectomy has become the standard of care for acute ischemic stroke due to large vessel occlusions. Racial differences in outcomes after mechanical thrombectomy for acute ischemic stroke have not been extensively studied. We evaluate the real-world evidence for differences between races in the outcomes of thrombectomy for large vessel occlusions using the NeuroVascular Quality Initiative-Quality Outcomes Database (NVQI-QOD). METHODS: Data from the NVQI-QOD acute ischemic stroke registry were analyzed and compared for racial differences in outcomes after mechanical thrombectomy in 4507 patients from 28 US centers (17 states) between January 2014 and April 2021. Race was dichotomized into non-Hispanic White (NHW, n=3649) and non-Hispanic Black (NHB, n=858). We performed 1:1 propensity score matching resulting in a subsample of matched groups (n=761 each for NHB and NHW) to compare study endpoints using Welch's two-sided t-tests and Χ2 test for continuous and categorical outcomes, respectively. RESULTS: Prior to matching, NHW and NHB patients significantly differed in age, comorbidities, medication use, smoking status, and presenting stroke severity. No significant difference in functional outcomes or mortality, at discharge or follow-up, were revealed. NHB patients had higher average postprocedure length of stay than NHW patients, which persisted following matching (11.2 vs 9.1 days, P=0.004). CONCLUSION: Evidence from the NVQI-QOD acute ischemic stroke registry showed that outcome metrics, such as modified Rankin Scale score and mortality, did not differ significantly between racial groups; however, disparity between NHW and NHB patients in postprocedure length of stay following mechanical thrombectomy was revealed.

3.
Epilepsy Behav ; 149: 109484, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37988904

RESUMO

BACKGROUND AND PURPOSE: Antiseizure medications (ASM) effectively prevent seizures in about 70% of adult epilepsy patients, but nonadherence to medication is the primary cause of breakthrough seizures, accounting for 26% to 79% of cases. Factors such as age, education, dosing frequency, forgetfulness, fear of side effects, and socioeconomic status contribute to poor adherence, especially among underserved populations. This study aimed to assess medication adherence during routine follow-up visits and identify the role of education in reducing non adherence in an underserved patient population. METHODS: The study involved a retrospective chart review of adult epilepsy patients seen at the University of Illinois Hospital between December 2016 and April 2020. Data on patient demographics, epilepsy and seizure classification, medication details, emergency visits, and adherence were collected from electronic medical records using the RedCap system. Descriptive statistics and statistical tests were conducted using STATA 17.0 for data analysis, including chi-squared analysis for categorical data and t-tests for continuous data. RESULTS: The study enrolled a total of 286 adult epilepsy patients who met the eligibility criteria. Among them, 111 patients (38.81 %) were classified as nonadherent based on ASM levels. Caucasian/white race and income > $50,000 per year, were significantly associated with adherence (p = 0.009 and p = 0.006 respectively). Moreover, patients with weekly seizures were more likely to be adherent (p = 0.042). No significant differences were found regarding medication adherence and sex, education, employment, epilepsy type, age at diagnosis, seizure type or number of current ASM medications. Even though not significant, a trend towards college educated patients being more adherent was observed (70.37 %). Of self-reported adherent patients, 33.33 % were found to be nonadherent based on ASM levels. Nurse phone calls reminding 70 non adherent patients about adherence increased the chances of becoming adherent by 80.39 %. Finally, although not statistically significant, the majority of adherent patients had no history of hospitalizations for breakthrough seizures (73.89 %). CONCLUSION: More than a third of our patients were found to be non-adherent during routine follow-up visits. Lower socio-economic status and lower education were associated with increased chances of being non adherent. Rates of adherence were improved by nurse's phone calls discussing the importance of adherence and risks of SUDEP. The findings emphasize the importance of education in improving medication adherence among these populations, suggesting the need for social interventions, community outreach programs, and targeted educational initiatives.


Assuntos
Epilepsia , Populações Vulneráveis , Adulto , Humanos , Estudos Retrospectivos , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Convulsões/tratamento farmacológico , Convulsões/epidemiologia , Adesão à Medicação
4.
Dalton Trans ; 52(39): 14151-14159, 2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37750312

RESUMO

Cu(I)-based coordination polymers (CPs) are known as efficient emissive materials providing an eco-friendly and cost-effective platform for the development of various functional materials and sensors. In addition to the nature of the metal center, organic ligands also play a crucial role in controlling the emissive properties of coordination polymers. Herein, we report on the synthesis of dithiane- and dithiolane-substituted triphenylamine ligands L1 and L2. These ligands were found to be emissive both in the solid state and in solution. In addition, these ligands exhibit solvatochromic behaviour due to the twisted intramolecular charge transfer (TICT) phenomenon. Next, coordination behaviour of these ligands was explored with Cu(I)X salts (X = Br and Cl) and four new 1D coordination polymers [{Cu(µ2-X)2Cu}(µ2-L)]n, CP1 (X = Br, L = L1), CP2 (X = Cl, L = L1), CP3 (X = Br, L = L2), and CP4 (X = Cl, L = L2) were synthesized and crystallographically characterized. The emission behaviour of all the CPs suggests ligand-centered transitions. On mechanical grinding, emission maxima (λem) for CP1 and CP2 were blue-shifted, whereas for CP3 and CP4 red-shifts were observed. All CPs were found to emit at 448 nm with increased intensity after grinding. It is supposed that grinding is responsible for a change in the spatial arrangement (dihedral angles) of the phenyl groups of triphenylamine, causing the observed emission shifts. Furthermore, the higher emission intensity after grinding suggests the occurrence of a similar phenomenon as an aggregation-induced quenching in these CPs.

5.
Annu Int Conf IEEE Eng Med Biol Soc ; 2022: 3459-3463, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-36086190

RESUMO

Subarachnoid hemorrhage (SAH) is a devastating neurological injury that can lead to many downstream complications including epilepsy. Predicting who will get epilepsy in order to find ways to prevent it as well as stratify patients for future interventions is a major challenge given the large number of variables not only related to the injury itself, but also to what happens after the injury. Extensive multimodal data are generated during the process of SAH patient care. In parallel, preclinical models are under development that attempt to imitate the variables observed in patients. Computational tools that consider all variables from both human data and animal models are lacking and demand an integrated, time-dependent platform where researchers can aggregate, store, visualize, analyze, and share the extensive integrated multimodal information. We developed a multi-tier web-based application that is secure, extensible, and adaptable to all available data modalities using flask micro-web framework, python, and PostgreSQL database. The system supports data visualization, data sharing and downloading for offline processing. The system is currently hosted inside the institutional private network and holds [Formula: see text] of data from 164 patients and 71 rodents. Clinical Relevance-Our platform supports clinical and preclinical data management. It allows users to comprehensively visualize patient data and perform visual analytics. These utilities can improve research and clinical practice for subarachnoid hemorrhage and other brain injuries.


Assuntos
Lesões Encefálicas , Epilepsia , Hemorragia Subaracnóidea , Animais , Lesões Encefálicas/complicações , Bases de Dados Factuais , Epilepsia/complicações , Humanos , Modelos Animais , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnóstico
6.
Eur J Pharmacol ; 927: 175054, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35636524

RESUMO

PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kß as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with ∼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.


Assuntos
Artrite Reumatoide , Fosfatidilinositol 3-Quinases , Artrite Reumatoide/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-Atividade
8.
J Med Chem ; 64(23): 17004-17030, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34843241

RESUMO

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Cálcio/metabolismo , Descoberta de Drogas , Administração Oral , Animais , Área Sob a Curva , Artrite Reumatoide/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacocinética , Ensaios Clínicos Fase I como Assunto , Humanos , Células Jurkat , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
9.
Neurosurgery ; 89(6): 1071-1079, 2021 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-34560777

RESUMO

BACKGROUND: Delayed cerebral vasospasm is a feared complication of aneurysmal subarachnoid hemorrhage (SAH). OBJECTIVE: To investigate the relationship of systemic inflammation, measured using the systemic immune-inflammation (SII) index, with delayed angiographic or sonographic vasospasm. We hypothesize that early elevations in SII index serve as an independent predictor of vasospasm. METHODS: We retrospectively reviewed the medical records of 289 SAH patients for angiographic or sonographic evidence of delayed cerebral vasospasm. SII index [(neutrophils × platelets/lymphocytes)/1000] was calculated from laboratory data at admission and dichotomized based on whether or not the patient developed vasospasm. Multivariable logistic regression and receiver operating characteristic (ROC) analysis were performed to determine the ability of SII index to predict the development of vasospasm. RESULTS: A total of 246 patients were included in our study, of which 166 (67.5%) developed angiographic or sonographic evidence of cerebral vasospasm. Admission SII index was elevated for SAH in patients with vasospasm compared to those without (P < .001). In univariate logistic regression, leukocytes, neutrophils, lymphocytes, neutrophil-lymphocyte ratio (NLR), and SII index were associated with vasospasm. After adjustment for age, aneurysm location, diabetes mellitus, hyperlipidemia, and modified Fisher scale, SII index remained an independent predictor of vasospasm (odds ratio 1.386, P = .003). ROC analysis revealed that SII index accurately distinguished between patients who develop vasospasm vs those who do not (area under the curve = 0.767, P < .001). CONCLUSION: Early elevation in SII index can independently predict the development of delayed cerebral vasospasm in aneurysmal SAH.


Assuntos
Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Inflamação/complicações , Linfócitos , Estudos Retrospectivos , Hemorragia Subaracnóidea/complicações , Vasoespasmo Intracraniano/diagnóstico por imagem , Vasoespasmo Intracraniano/etiologia
10.
Stroke ; 52(4): 1339-1346, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33657859

RESUMO

BACKGROUND AND PURPOSE: We investigated the prevalence, awareness, and control of vascular risk factors (VRFs) and the use of antithrombotic and statin agents in HCHS (Hispanic Community Health Study)/SOL (Study of Latinos) participants with self-reported history of stroke or transient ischemic attack. METHODS: Sociodemographic characteristics, medications, and prevalence of different VRFs were recorded. VRF diagnoses and goals were based on the recommendations of professional organizations. Factors associated with optimal VRF control and use of antithrombotic and statin agents were investigated using multivariate logistic regression. RESULTS: The analysis included 404 participants (39% men). The prevalences of hypertension, dyslipidemia, and diabetes were 59%, 65%, and 39%, respectively. Among those who met the diagnostic criteria for these diagnoses, the frequencies of awareness were 90%, 75%, and 83%, respectively. In participants who were aware of their VRFs, the prevalences of controlled hypertension, dyslipidemia, and diabetes were 46%, 32%, and 54%. Approximately 46% of the participants were on antithrombotics, 39% on statins, and 26% on both. Only 38% of those with atrial fibrillation received anticoagulation. In multivariate analyses adjusted for baseline sociodemographic characteristics, older age was associated with uncontrolled hypertension and diabetes. Residing in the United States for ≥10 years and born in the United States were associated with uncontrolled diabetes, female sex with uncontrolled dyslipidemia, and lack of health insurance with decreased use of statins and hyperlipidemia. CONCLUSIONS: Hispanic/Latino adults in the United States have high prevalence and awareness of VRFs but low adherence to secondary stroke prevention strategies. Older adults, women, and uninsured people are vulnerable groups that may benefit from targeted interventions. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060344.


Assuntos
Doenças Cardiovasculares/epidemiologia , Fibrinolíticos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle , Idoso , Doenças Cardiovasculares/complicações , Estudos de Coortes , Feminino , Hispânico ou Latino , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Prevenção Secundária/métodos , Prevenção Secundária/estatística & dados numéricos , Acidente Vascular Cerebral/etiologia , Estados Unidos
11.
Stroke ; 51(11): 3295-3301, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33032489

RESUMO

BACKGROUND AND PURPOSE: The role of regional hypoperfusion as a contributor to stroke risk in atherosclerotic vertebrobasilar disease has recently been confirmed by the observational VERiTAS (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke) Study. We examined the stability of hemodynamic status over time and its relationship to stroke risk in patients from this prospective cohort. METHODS: VERiTAS enrolled patients with recently symptomatic ≥50% atherosclerotic stenosis/occlusion of vertebral and/or basilar arteries. Large vessel flow in the vertebrobasilar territory was assessed using quantitative magnetic resonance angiography, and patients were designated as low or normal flow based on distal territory regional flow, incorporating collateral capacity. Patients underwent standard medical management and follow-up for primary outcome event of vertebrobasilar territory stroke. Quantitative magnetic resonance angiography imaging was repeated at 6, 12, and 24 months. Flow status over time was examined relative to baseline and relative to subsequent stroke risk using a cause-specific proportional hazard model, with flow status treated as a time-varying covariate. Mean blood pressure was examined to assess for association with changes in flow status. RESULTS: Over 19±8 months of follow-up, 132 follow-up quantitative magnetic resonance angiography studies were performed in 58 of the 72 enrolled patients. Of the 13 patients with serial imaging who had low flow at baseline, 7 (54%) had improvement to normal flow at the last follow-up. Of the 45 patients who had normal flow at baseline, 3 (7%) converted to low flow at the last follow-up. The mean blood pressure did not differ in patients with or without changes in flow status. The time-varying flow status remained a strong predictor of subsequent stroke (hazard ratio, 10.3 [95% CI, 2.2-48.7]). CONCLUSIONS: There is potential both for improvement and worsening of hemodynamics in patients with atherosclerotic vertebrobasilar disease. Flow status, both at baseline and over time, is a risk factor for subsequent stroke, thus serving as an important prognostic marker. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00590980.


Assuntos
Circulação Cerebrovascular , Hemodinâmica , Arteriosclerose Intracraniana/fisiopatologia , AVC Isquêmico/epidemiologia , Insuficiência Vertebrobasilar/fisiopatologia , Idoso , Estudos de Coortes , Feminino , Humanos , Arteriosclerose Intracraniana/diagnóstico por imagem , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Insuficiência Vertebrobasilar/diagnóstico por imagem
12.
Muscle Nerve ; 62(6): 717-721, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32856738

RESUMO

INTRODUCTION: Ulnar neuropathy at the elbow (UNE) is the second most common entrapment neuropathy. Our goal was to create and analyze a grading system for UNE electrodiagnostic severity. METHODS: We retrospectively analyzed EMG reports with UNE. We then classified 112 limbs as having mild, moderate, or severe grade UNE based on electrodiagnostic findings. The association between presenting symptoms and signs, EMG findings, treatment type, and electrodiagnostic grade was statistically analyzed. RESULTS: Seventeen limbs (15.2%) had mild, 80 (71.4%) had moderate, and 15 (13.4%) had severe UNE. Symptoms (P = .016), exam findings (P < .001), and treatment type (P = .043) were significantly associated with electrodiagnostic grade. DISCUSSION: Our UNE grading system was significantly related to symptoms, physical exam, and treatment selection and may be useful to measure electrodiagnostic severity.


Assuntos
Potenciais de Ação , Eletromiografia , Condução Nervosa , Síndromes de Compressão do Nervo Ulnar/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cotovelo , Eletrodiagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Síndromes de Compressão do Nervo Ulnar/diagnóstico , Neuropatias Ulnares/diagnóstico , Neuropatias Ulnares/fisiopatologia
13.
Epilepsy Behav ; 111: 107228, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32599431

RESUMO

PURPOSE: People with epilepsy (PWE) come from a wide variety of social backgrounds and educational skillsets, making self-management (SM) education for improving their condition challenging. Here, we evaluated whether a mobile technology-based personalized epilepsy SM education intervention, PAUSE to Learn Your Epilepsy (PAUSE), improves SM measures such as self-efficacy, epilepsy SM behaviors, epilepsy outcome expectations, quality of life (QOL), and personal impact of epilepsy in adults with epilepsy. METHODS: Recruitment for the PAUSE study occurred from October 2015 to March 2019. Ninety-one PWE were educated using an Internet-enabled computer tablet application that downloads custom, patient-specific educational programs from Epilepsy.com. Validated self-reported questionnaires were used for outcome measures. Participants were assessed at baseline (T0), the first follow-up at completion of the PWE-paced 8-12-week SM education intervention (T1), and the second follow-up at least 3 months after the first follow-up (T2). Multiple linear regression was used to assess within-subject significant changes in outcome measures between these time points. RESULTS: The study population was diverse and included individuals with a wide variety of SM educational needs and abilities. The median time for the first follow-up assessment (T1) was approximately 4 months following the baseline (T0) and 8 months following baseline for the second follow-up assessment (T2). Participants showed significant improvement in all SM behaviors, self-efficacy, outcome expectancy, QOL, and personal impact of epilepsy measures from T0 to T1. Participants who scored lower at baseline tended to show greater improvement at T1. Similarly, results showed that participant improvement was sustained in the majority of SM measures from T1 to T2. CONCLUSION: This study demonstrated that a mobile technology-based personalized SM intervention is feasible to implement. The results provide evidence that epilepsy SM behavior and practices, QOL, outcome expectation for epilepsy treatment and management, self-efficacy, and outcome expectation and impact of epilepsy significantly improve following a personalized SM education intervention. This underscores a greater need for a pragmatic trial to test the effectiveness of personalized SM education, such as PAUSE to Learn Your Epilepsy, in broader settings specifically for the unique needs of the hard-to-reach and hard-to-treat population of PWE.


Assuntos
Escolaridade , Epilepsia/psicologia , Qualidade de Vida/psicologia , Autogestão/psicologia , Classe Social , Telemedicina/métodos , Adulto , Epilepsia/terapia , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Autoeficácia , Autogestão/métodos , Inquéritos e Questionários
14.
J Am Heart Assoc ; 9(12): e016406, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32500810

RESUMO

Background Atherosclerotic vertebrobasilar disease is a significant etiology of posterior circulation stroke. The prospective observational VERiTAS (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke) study demonstrated that distal hemodynamic status is a robust predictor of subsequent vertebrobasilar stroke risk. We sought to compare predictive models using thresholds for posterior circulation vessel flows standardized to age and vascular anatomy to optimize risk prediction. Methods and Results VERiTAS enrolled patients with recent vertebrobasilar transient ischemic attack or stroke and ≥50% atherosclerotic stenosis/occlusion in vertebral and/or basilar arteries. Quantitative magnetic resonance angiography measured large-vessel vertebrobasilar territory flow, and patients were designated as low or normal flow based on a prespecified empiric algorithm considering distal territory regional flow and collateral capacity. For the present study, post hoc analysis was performed to generate additional predictive models using age-specific normalized flow measurements. Sensitivity, specificity, and time-to-event analyses were compared between the algorithms. The original prespecified algorithm had 50% sensitivity and 79% specificity for future stroke risk prediction; using a predictive model based on age-normalized flows in the basilar and posterior cerebral arteries, standardized to vascular anatomy, optimized flow status thresholds were identified. The optimized algorithm maintained sensitivity and increased specificity to 84%, while demonstrating a larger and more significant hazard ratio for stroke on time-to-event analysis. Conclusions These results indicate that flow remains a strong predictor of stroke across different predictive models, and suggest that prediction of future stroke risk can be optimized by use of vascular anatomy and age-specific normalized flows.


Assuntos
Angiografia Cerebral , Circulação Cerebrovascular , Hemodinâmica , Ataque Isquêmico Transitório/etiologia , AVC Isquêmico/etiologia , Angiografia por Ressonância Magnética , Insuficiência Vertebrobasilar/diagnóstico por imagem , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Velocidade do Fluxo Sanguíneo , Feminino , Humanos , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/fisiopatologia , AVC Isquêmico/diagnóstico , AVC Isquêmico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Estados Unidos , Insuficiência Vertebrobasilar/complicações , Insuficiência Vertebrobasilar/fisiopatologia
15.
J Med Chem ; 63(11): 6107-6133, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32368909

RESUMO

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.


Assuntos
Cromanos/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Animais , Cromanos/farmacocinética , Cromanos/uso terapêutico , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
16.
Cerebrovasc Dis Extra ; 9(3): 123-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618729

RESUMO

INTRODUCTION: Distal territory blood flow is independently associated with subsequent strokes in symptomatic vertebrobasilar atherosclerotic disease. We aimed to assess infarct patterns in relation to hemodynamic status in the prospective Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS) study. METHODS: Distal territory blood flow was measured using quantitative magnetic resonance angiography (MRA) in 72 patients with symptomatic atherosclerotic vertebrobasilar disease, and then dichotomized into normal (n = 54) and low (n = 18) flow. Patients were followed longitudinally on standard medical management. Two observers blinded to flow status independently reviewed the imaging performed at the time of subsequent strokes, in order to adjudicate the likely mechanism based on infarct patterns. The frequency of stroke mechanisms was qualitatively compared based on flow status. RESULTS: During a median follow-up period of 23 months, 10/72 patients had a subsequent stroke; 5 of these had low distal flow. Infarct patterns were adjudicated to be consistent with hemodynamic (n = 2), embolic (n = 4), and junctional plaque/perforator (n = 4) infarcts. Hemodynamic infarcts were seen in 40% (2/5) low-flow patients, in comparison to 0% (0/5) normal-flow patients. CONCLUSION: In contrast to normal-flow patients, those with low distal flow seem to be uniquely susceptible to hemodynamic infarctions, although other patterns of infarction can also be seen in these hemodynamically impaired patients.


Assuntos
Aterosclerose/complicações , Infarto Encefálico/etiologia , Circulação Cerebrovascular , Hemodinâmica , Insuficiência Vertebrobasilar/complicações , Aterosclerose/diagnóstico por imagem , Aterosclerose/fisiopatologia , Velocidade do Fluxo Sanguíneo , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/fisiopatologia , Angiografia Cerebral/métodos , Feminino , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Estados Unidos , Insuficiência Vertebrobasilar/diagnóstico por imagem , Insuficiência Vertebrobasilar/fisiopatologia
17.
Epilepsia ; 60(9): 1921-1931, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31486072

RESUMO

OBJECTIVE: To assess depressive symptom outcomes in a pooled sample of epilepsy self-management randomized controlled trials (RCTs) from the Managing Epilepsy Well (MEW) Network integrated research database (MEW DB). METHODS: Five prospective RCTs involving 453 adults with epilepsy compared self-management intervention (n = 232) versus treatment as usual or wait-list control outcomes (n = 221). Depression was assessed with the nine-item Patient Health Questionnaire. Other variables included age, gender, race, ethnicity, education, income, marital status, seizure frequency, and quality of life. Follow-up assessments were collapsed into a visit 2 and a visit 3; these were conducted postbaseline. RESULTS: Mean age was 43.5 years (SD = 12.6), nearly two-thirds were women, and nearly one-third were African American. Baseline sample characteristics were mostly similar in the self-management intervention group versus controls. At follow-up, the self-management group had a significantly greater reduction in depression compared to controls at visit 2 (P < .0001) and visit 3 (P = .0002). Quality of life also significantly improved in the self-management group at visit 2 (P = .001) and visit 3 (P = .005). SIGNIFICANCE: Aggregate MEW DB analysis of five RCTs found depressive symptom severity and quality of life significantly improved in individuals randomized to self-management intervention versus controls. Evidence-based epilepsy self-management programs should be made more broadly available in neurology practices.


Assuntos
Adaptação Psicológica/fisiologia , Depressão/complicações , Depressão/diagnóstico , Epilepsia/complicações , Qualidade de Vida , Autogestão , Adulto , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
18.
Epilepsy Behav ; 98(Pt A): 258-265, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31398690

RESUMO

PURPOSE: People with epilepsy (PWE) from underserved populations face significant barriers to epilepsy management and therefore may lack knowledge about epilepsy and self-management (SM) of epilepsy. This paper evaluates SM practices, self-efficacy, outcome expectancy, quality of life, and personal impact of epilepsy in PWE from underserved populations as compared with all PWE. METHODS: Recruitment for the Managing Epilepsy Well (MEW) Network PAUSE to Learn Your Epilepsy study occurred from October 2015 to March 2019. Participants were assessed at baseline; after SM education intervention; and 6-, 9-, and 15-month postbaseline assessment. Baseline data from 112 PWE were analyzed for this report. RESULTS: Study population was diverse: 63% were women, 47.3% were non-Hispanic black, 24.1% were Hispanic, and 57.4% had public healthcare coverage. Participants on average had epilepsy for 14 years, and 49.1% reported at least one seizure within the past month, but only 27% reported having used a seizure diary or calendar for seizure tracking. Self-management practices & behaviors were significantly lower among PWE from underserved populations than all PWE, though self-efficacy among PWE from underserved populations was significantly higher. CONCLUSION: This study identifies the unique epilepsy SM needs of PWE from underserved populations. We discuss the need for a personalized approach for developing SM skills and behaviors among these PWE.


Assuntos
Epilepsia/psicologia , Medicina de Precisão/psicologia , Qualidade de Vida/psicologia , Autoeficácia , Autogestão/psicologia , Populações Vulneráveis/psicologia , Adolescente , Adulto , Idoso , Epilepsia/economia , Epilepsia/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Medicina de Precisão/economia , Medicina de Precisão/métodos , Autogestão/economia , Autogestão/métodos , Adulto Jovem
19.
J Org Chem ; 84(20): 12800-12808, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31321982

RESUMO

Nickel-catalyzed regioselective C(2)-H arylation of indoles and pyrroles with aryl chlorides is achieved under neat conditions. This method allows the efficient coupling of diverse aryl chlorides employing a user-friendly and inexpensive Ni(OAc)2/dppf catalyst system at 80 °C. Numerous functionalities, such as halides, alkyl ether, fluoro-alkyl ether, and thioether, and substituted amines, including heteroarenes like benzothiazolyl, pyrrolyl, indolyl, and carbazolyl, are well tolerated under the reaction conditions. The preliminary mechanistic study highlights a single-electron transfer (SET) pathway for the arylation reaction.

20.
Chem Sci ; 10(41): 9493-9500, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-32110305

RESUMO

A mild and efficient nickel-catalyzed method for the coupling of unactivated primary and secondary alkyl chlorides with the C-H bond of indoles and pyrroles is described which demonstrates a high level of chemo and regioselectivity. The reaction tolerates numerous functionalities, such as halide, alkenyl, alkynyl, ether, thioether, furanyl, pyrrolyl, indolyl and carbazolyl groups including acyclic and cyclic alkyls under the reaction conditions. Mechanistic investigation highlights that the alkylation proceeds through a single-electron transfer (SET) process with Ni(i)-species being the active catalyst. Overall, the alkylation follows a Ni(i)/Ni(iii) pathway involving the rate-influencing two-step single-electron oxidative addition of alkyl chlorides.

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