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1.
J Child Neurol ; : 883073819901228, 2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32065003

RESUMO

Children and adults with genetic generalized epilepsy may have focal clinical seizure symptoms as well as electroencephalographic (EEG) findings. This may pose a diagnostic challenge to clinicians, especially when concomitant focal neuroimaging findings exist and the epilepsy is medically refractory. We sought to highlight the challenges that clinicians may face through the description of 2 children with suspected genetic generalized epilepsy who had both focal seizure symptoms and EEG/neuroimaging findings and underwent invasive EEG monitoring. Ultimately, invasive monitoring failed to demonstrate a focal origin for the seizures in both cases, and instead confirmed the presence of genetic generalized epilepsy. We demonstrate that ≥3-Hz generalized monomorphic spike and waves are less likely to represent secondary bilateral synchrony, that focal neuroimaging findings may not always be causal and that repeated hyperventilation is an essential activation procedure for genetic generalized epilepsy.

2.
Pharm Res ; 37(3): 43, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31989336

RESUMO

PURPOSE: Pyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia. METHODS: ALL cells were treated with PP at various concentrations to determine its effect on cell proliferation. Metabolic function was tested by evaluating Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR). Lastly, 3D spheroids were grown, and PP was reformulated into nanoparticles to evaluate distribution effectiveness. RESULTS: PP was found to inhibit ALL proliferation, with varied selectivity to different ALL cell subtypes. We also found that PP's cell death activity was specific for leukemic cells, as primary normal immune cells were resistant to PP-mediated cell death. Metabolic studies indicated that PP, in part, inhibits mitochondrial oxidative phosphorylation. To increase the targeting of PP to a hypoxic bone tumor microenvironment (BTME) niche, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. CONCLUSION: We have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells and can be effectively formulated into a nanoparticle delivery system to target the BTME.

4.
Eur Urol ; 77(1): 110-118, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31740072

RESUMO

BACKGROUND: The long-term oncological outcomes of laparoscopic (LRC) and robotic-assisted radical cystectomy (RARC) are still maturing compared with open radical cystectomy (ORC). OBJECTIVE: To evaluate the 5-yr oncological outcomes of patients recruited into the randomised trial of Open, Laparoscopic and Robot Assisted Cystectomy (CORAL) and extracorporeal urinary diversion. DESIGN, SETTING, AND PARTICIPANTS: A review of prospectively maintained database of 60 patients with muscle-invasive bladder cancer (MIBC) or high-risk nonmuscle-invasive bladder cancer (HRNMIBC) who were previously randomised in the CORAL trial to receive ORC, RARC, or LRC. This trial was designed to compare the perioperative and early oncological outcomes of these techniques. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcomes of interest included 5-yr recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Kaplan-Meier curves were used to plot the recurrence and survival data. The curves between RFS, CSS, and OS were compared using the log-rank test. A two-sided p value <0.05 was considered significant. Results were analysed on the basis of intention to treat. RESULTS AND LIMITATIONS: A total of 60 patients with either MIBC (n=38) or HRNMIBC (n=21) were randomised in the CORAL trial to receive ORC, RARC, or LRC. The 5-yr RFS was 60%, 58%, and 71%; 5-yr CSS was 64%, 68%, and 69%; and 5-yr OS was 55%, 65%, and 61% for ORC, RARC, and LRC, respectively. There was no significant difference in RFS, CSS, and OS between the three surgical arms. The principal limitation is the small sample size. CONCLUSIONS: There was no difference in 5-yr RFS, CSS, and OS rates of patients who underwent ORC, RARC, and LRC for management of bladder cancer. Minimally invasive techniques achieved equivalent oncological outcomes to the gold standard of ORC. However, the study was based at a single institution with a small sample size. PATIENT SUMMARY: Patients who agreed to participate in the randomised trial of either open, laparoscopic, or robotic-assisted radical cystectomy for bladder cancer did not have different cancer outcomes at 5yr.

5.
Sci Rep ; 9(1): 18177, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796785

RESUMO

The failure of lung cancer treatments has been attributed mostly to the development of drug resistance, however the underlying cellular and molecular mechanisms are poorly understood. Cancer initiating stem cells (CSCs), present in tumors in a small percentage, play critical roles in the development of drug resistance, metastasis, and cancer relapse. Hence, novel treatments targeting both bulk cancer cells and CSCs are under intense investigation. Herein, we report that lung cancer cells grown on a 3D fibrous scaffold form tumoroids that resemble in vivo tumors, expand CSCs, and provide a platform to identify anti-CSC drugs. The screening of an NCI library of FDA-approved drugs using tumoroid cultures led to identification of Actinomycin D (AD) as a top CSC inhibitor. Since CSCs are mostly resident in the tumor's inner core, AD was combined with an angiotensin receptor antagonist, Telmisartan (TS), which is known to increase drug permeability in tumors and was shown to have anti-CSC activity. Our results showed that AD + TS administered intra-tumorally was significantly more effective than either drug alone in both syngeneic and xenograft mouse models. The results of mechanistic studies revealed that CSC expansion in tumoroids was associated with activation of ß catenin signaling and that AD + TS treatment reduced active ß catenin levels in tumors. Together, these results establish the utility of the tumoroid culture system to expand CSCs ex vivo for targeted drug screening, to identify promising novel treatments with both anti-CSC and anti-cancer effects, and to individualize treatments for metastatic drug resistant lung cancer patients.

6.
Eur Urol Oncol ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31668714

RESUMO

CONTEXT: The complexity of bladder cancer diagnosis and staging results in delays in definitive treatment of muscle-invasive bladder cancer by radical cystectomy. OBJECTIVE: This systematic review and meta-analyses aim to assess the impact of delays in radical cystectomy. EVIDENCE ACQUISITION: A systematic review was conducted by searching Medline and Ovid Gateway using protocol-driven search terms in August 2019, with no time limit on the studies included. The identified studies were assessed according to strict criteria and using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist and Risk of Bias in Non-randomised Studies-of Interventions (ROBINS-I) tool. Meta-analyses were conducted based on the type of delay. Random-effect models were used whereby the presence of a delay was the exposure variable and overall survival was the outcome of interest, for which pooled hazard ratios were calculated. EVIDENCE SYNTHESIS: Nineteen studies were eligible for inclusion (17 532 patients), of which 10 were included in the meta-analyses. A longer delay between bladder cancer diagnosis and radical cystectomy resulted in a pooled hazard ratio of 1.34 (95% confidence interval [CI]: 1.18-1.53) for overall death. For a delay between transurethral resection and cystectomy, we found a pooled hazard ratio of 1.18 (95% CI: 0.99-1.41) for overall death. A pooled hazard ratio of 1.04 (95% CI: 0.93-1.16) was calculated for a longer delay between neoadjuvant chemotherapy and radical cystectomy. CONCLUSIONS: A delay in radical cystectomy after diagnosis was found to have a significantly detrimental effect on overall survival for bladder cancer patients. However, there was huge heterogeneity in how a delay was defined. PATIENT SUMMARY: In this review, we investigated the effect of a delay in radical treatment on survival. This review highlights the importance of scheduling radical cystectomies in a timely manner whilst monitoring factors such as comorbidities and scheduling, in order to treat patients requiring radical cystectomy without delay.

8.
J Biopharm Stat ; 29(5): 749-759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31590626

RESUMO

A question that routinely arises in medical device clinical studies is the homogeneity across demographic subgroups, geographical regions, or investigational sites of the enrolled patients in terms of treatment effects or outcome variables. The main objective of this paper is to discuss statistical concepts and methods for the assessment of such homogeneity and to provide the practitioner a statistical framework and points to consider in conducting homogeneity assessment. Demographic subgroups, geographical regions, and investigational sites are discussed separately as each has its unique issues. Specific considerations are also given to randomized controlled trials, non-randomized comparative studies, and single-arm studies. We point out that judicious use of statistical methods, in conjunction with sound clinical judgment, is essential in handling the issue of homogeneity of treatment effect in medical device clinical studies.

10.
BMJ Open Qual ; 8(2): e000396, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31321314

RESUMO

Background: The Vancouver Island Health Authority (VIHA) implemented a standard advance care planning (ACP) document called the medical order for scope of treatment (MOST) in February 2016 to improve end of life communication and documentation. This study aims to see if the MOST implementation improves inpatient ACP documentation when compared with the 'do not resuscitate' (DNR) order. Improvement is measured by: (1) proportion of inpatients with documented orders for life-sustaining treatment, (2) discordance between patient's expressed wishes and chart documentation, (3) patient satisfaction and (4) days admitted to an acute care hospital within 90 days of study inclusion. Methods: We performed a single-centre quality improvement study tracking the effects of MOST implementation. 329 consecutive patients were enrolled at a 215-bed community hospital located in Comox, British Columbia, Canada. Results: The MOST integrated well into the process of care, significantly improving ACP documentation from 33% preimplementation to 100% over 8 months of implementation. MOST completion was associated with a significant decrease in discordance between patients' wishes and documented goals of care. Patients with a MOST were significantly older and had a higher charlson comorbidity score than those without a MOST. Despite this, there was no difference in the number of days study patients were admitted to hospital within 90 days of study inclusion. Conclusions: MOST implementation improves the frequency and quality of inpatient ACP documentation with no effect on acute care utilisation.

16.
Can J Neurol Sci ; 46(5): 559-565, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31292009

RESUMO

OBJECTIVE: Focal cortical dysplasia (FCD) is a common cause of refractory, focal onset epilepsy in children. Interictal, scalp electroencephalograph (EEG) markers have been associated with these pathologies and epilepsy surgery may be an option for some patients. We aim to study how scalp EEG and magnetic resonance imaging (MRI) markers of FCD affect referral of these patients for surgical evaluation. METHODS: A single-center, retrospective review of children with focal onset epilepsy. Patients were included if they were between 1 month and 18 years of age, had focal onset seizures, prolonged scalp EEG monitoring, and an MRI conducted after 2 years of age. Statistics were carried out using the chi-squared and student's t-test, as well as a logistic regression model. RESULTS: Sixty-eight patients were included in the study. Thirty-seven of these patients were referred to a comprehensive pediatric epilepsy program (CPEP) for surgical evaluation, and of these 22% showed FCD EEG markers, 32% FCD MRI markers, and 10% had both. These markers were also present in patients not referred to a CPEP. The MRI markers were significantly associated with CPEP referral, whereas EEG markers were not. Neither marker type was associated with epilepsy surgery. CONCLUSION: This study found that children with focal onset epilepsy were more likely to be referred for surgical evaluation if they were medically refractory, or were diagnosed with FCD or tumor on MRI. Scalp EEG markers of FCD were not associated with CPEP referral. The online tool CASES may be a useful physician guide for identifying appropriate children for epilepsy surgery referral.

17.
BMJ Qual Saf ; 28(11): 887-893, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31201226

RESUMO

BACKGROUND: Patients and their families often have an inadequate understanding of the risks and benefits of their advance care planning (ACP) options. Improving patients' knowledge of therapeutic interventions allows them to better select treatments they believe are most appropriate for their condition. OBJECTIVES: To determine if a video aimed at educating and engaging hospitalised patients on a standardised ACP order set can improve (1) inpatient understanding of key ACP concepts, (2) ACP documentation within 48 hours of hospital admission, (3) concordance between a patient's expressed and chart-documented care preferences, (4) patient satisfaction with decision-making, and (5) patient's decisional confidence. METHODS: A prospective, non-randomised, pre-post intervention study of 252 inpatients in a 215-bed community-based hospital in Comox, British Columbia, Canada. RESULTS: Our video decision support tool was associated with significant improvements in (1) patient understanding of key ACP concepts (70%-100%; p<0.0001), (2) ACP documentation within 48 hours of hospital admission (81%-92%; p=0.01), (3) concordance between patients' expressed wishes and chart documentation (69%-89%; p<0.0001), (4) patient satisfaction with decision-making (Canadian Health Care Evaluation Project Lite score: 4.3-4.5, p=0.001), and (5) patient's decisional confidence (patients with no decisional conflict, increased from 72% to 93%; p<0.0001). CONCLUSION: A 13 min video aimed at educating and engaging inpatients on ACP concepts improved patient understanding of key ACP concepts, rates of ACP documentation and patient satisfaction with decision-making.

18.
BMJ Open ; 9(4): e025979, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133622

RESUMO

OBJECTIVES: We provide new estimates on size, composition and distribution of human resource for health in India and compare with the health workers population ratio as recommended by the WHO. We also estimate size of non-health workers engaged in health sector and the size of technically qualified health professionals who are not a part of the health workforce. DESIGN: Nationally representative cross-section household survey and review of published documents by the Central Bureau of Health Intelligence. SETTING: National. PARTICIPANTS: Head of household/key informant in a sample of 101 724 households. INTERVENTIONS: Not applicable. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the number and density of health workers,and the secondary outcome was the percentage of health workers who are technically qualified and the percentage of individuals technically qualified and not in workforce. RESULTS: The total size of health workforce estimated from the National Sample Survey (NSS) data is 3.8 million as of January 2016, which is about 1.2 million less than the total number of health professionals registered with different councils and associations. The density of doctors and nurses and midwives per 10 000 population is 20.6 according to the NSS and 26.7 based on the registry data. Health workforce density in rural India and states in eastern India is lower than the WHO minimum threshold of 22.8 per 10 000 population. More than 80% of doctors and 70% of nurses and midwives are employed in the private sector. Approximately 25% of the currently working health professionals do not have the required qualifications as laid down by professional councils, while 20% of adequately qualified doctors are not in the current workforce. CONCLUSIONS: Distribution and qualification of health professionals are serious problems in India when compared with the overall size of the health workers. Policy should focus on enhancing the quality of health workers and mainstreaming professionally qualified persons into the health workforce.

19.
J Pharmacol Exp Ther ; 370(1): 25-34, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31010844

RESUMO

Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)-resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C 1) was not crossresistant to vincristine or methotrexate; 2) showed a similar proliferation rate and cell surface marker expression as parental REH; 3) demonstrated decreased chemotaxis toward bone marrow stromal cells; and 4) expressed higher transcript levels of cytidine deaminase (CDA) and mitoNEET (CISD1) than the parental REH cell line. Based on these findings, we tested NL-1, a mitoNEET inhibitor, which induced a concentration-dependent decrease in cell viability with a comparable IC50 value in REH and REH/Ara-C. Furthermore, NL-1 decreased cell viability in six different ALL cell lines and showed inhibitory activity in a hemosphere assay. NL-1 also impaired the migratory ability of leukemic cells, irrespective of the chemoattractant used, in a chemotaxis assay. More importantly, NL-1 showed specific activity in inducing death in a drug-resistant population of leukemic cells within a coculture model that mimicked the acquired resistance and de novo resistance observed in the bone marrow of relapsed patients. Subsequent studies indicated that NL-1 mediates autophagy, and inhibition of autophagy partially decreased NL-1-induced tumor cell death. Finally, NL-1 showed antileukemic activity in an in vivo mouse ALL model. Taken together, our study demonstrates that mitoNEET has potential as a novel antileukemic drug target in treatment refractory or relapsed ALL.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiotaxia/efeitos dos fármacos , Citarabina/farmacologia , Descoberta de Drogas , Humanos , Ligantes , Proteínas Mitocondriais/antagonistas & inibidores , Recidiva
20.
Proc (Bayl Univ Med Cent) ; 32(1): 30-33, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30956576

RESUMO

The no-reflow phenomenon occurs in a considerable number of patients with ST elevation myocardial infarction (STEMI) undergoing primary reperfusion therapy. Our study aimed to identify clinical, angiographic, and procedural variables that predict this phenomenon in patients with STEMI undergoing primary percutaneous coronary intervention (PPCI), as well as determine the impact of no-reflow on in-hospital mortality. Prospective observational data from 410 patients with STEMI undergoing PPCI were obtained. In this study, diabetes mellitus, late presentation, higher Killip class at admission, anterior wall infarction, proximal site of occlusion, presence of high-grade thrombus, and left ventricular systolic dysfunction at admission were significantly associated with suboptimal coronary flow. Diabetes mellitus, a high thrombus burden, prolonged total ischemic time, and low left ventricular ejection fraction on admission were independent predictors of no-reflow. No-reflow during PPCI was associated with in-hospital mortality more than twice that for normal flow.

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