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  • 1
    Publication Date: 2018-01-12
    Description: Objectives Ischaemic heart diseases (IHDs) are a leading cause of death worldwide. Although prescribing according to guidelines improves health outcomes, it remains suboptimal. We determined whether interventions targeted at healthcare professionals are effective to enhance prescribing and health outcomes in patients with IHDs. Methods We systematically searched PubMed and EMBASE for studies published between 1 January 2000 and 31 August 2017. We included original studies of interventions targeted at healthcare professionals to enhance prescribing guideline-recommended medications for IHDs. We only included randomised controlled trials (RCTs). Main outcomes were the proportion of eligible patients receiving guideline-recommended medications, the proportion of patients achieving target blood pressure and target low-density lipoprotein-cholesterol (LDL-C)/cholesterol level and mortality rate. Meta-analyses were performed using the inverse-variance method and the random effects model. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Results We included 13 studies, 4 RCTs (1869 patients) and 9 cluster RCTs (15 224 patients). 11 out of 13 studies were performed in North America and Europe. Interventions were of organisational or professional nature. The interventions significantly enhanced prescribing of statins/lipid-lowering agents (OR 1.23; 95% CI 1.07 to 1.42, P=0.004), but not other medications (aspirin/antiplatelet agents, beta-blockers, ACE inhibitors/angiotensin II receptor blockers and the composite of medications). There was no significant association between the interventions and improved health outcomes (target LDL-C and mortality) except for target blood pressure (OR 1.46; 95% CI 1.11 to 1.93; P=0.008). The evidence was of moderate or high quality for all outcomes. Conclusions Organisational and professional interventions improved prescribing of statins/lipid-lowering agents and target blood pressure in patients with IHDs but there was little evidence of change in other outcomes. PROSPERO registration number CRD42016039188 .
    Keywords: Open access
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 2
    Publication Date: 2018-11-02
    Description: Purpose: The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma (GBM). Experimental Design: Gene set enrichment, LC/MS, and extracellular flux analyses were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency. Results: Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro and in multiple xenograft models in vivo . ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1 hour, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3β at serine 9. GSK3β promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone-induced apoptosis in stem-like GBM cells in vitro and in vivo . Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction in vitro and in vivo . Conclusions: These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies. Clin Cancer Res; 24(21); 5392–406. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 3
    Publication Date: 2018-12-15
    Description: Purpose: Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi. Experimental Design: Tumors from patients with BRAF wild-type (WT), V600E (class I), and L597S (class II) metastatic melanoma were used to generate patient-derived xenografts (PDX). We assembled a panel of melanoma cell lines with class IIa (activation segment) or IIb (p-loop) mutations and compared these with WT or V600E/K BRAF mutant cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib, and LY3009120), MEKi (cobimetinib, trametinib, and binimetinib), or the combination. We identified 2 patients with BRAF L597S metastatic melanoma who were treated with dMAPKi. Results: BRAFi impaired MAPK signaling and cell growth in class I and II BRAF mutant cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor regression in two melanoma PDXs with class II BRAF mutations and prolonged survival of mice with class II BRAF mutant melanoma brain metastases. Two patients with BRAF L597S mutant melanoma clinically responded to dMAPKi. Conclusions: Class II BRAF mutant melanoma is growth inhibited by dMAPKi. Responses to dMAPKi have been observed in 2 patients with class II BRAF mutant melanoma. These data provide rationale for clinical investigation of dMAPKi in patients with class II BRAF mutant metastatic melanoma. See related commentary by Johnson and Dahlman, p. 6107 .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 4
    Publication Date: 2018-06-02
    Description: Purpose: Glioblastoma (GBM) is the most common primary central nervous system cancer in adults. Oncolytic HSV-1 (oHSV) is the first FDA-approved gene therapy approach for the treatment of malignant melanoma. For GBM, oHSVs need to be engineered to replicate within and be toxic to the glial tumor but not to normal brain parenchymal cells. We have thus engineered a novel oHSV to achieve these objectives. Experimental Design: NG34 is an attenuated HSV-1 with deletions in the genes encoding viral ICP6 and ICP34.5. These mutations suppress virus replication in nondividing brain neurons. NG34 expresses the human GADD34 gene under transcriptional control of a cellular Nestin gene promoter/enhancer element, whose expression occurs selectively in GBM. In vitro cytotoxicity assay and survival studies with mouse models were performed to evaluate therapeutic potency of NG34 against glioblastoma. In vivo neurotoxicity evaluation of NG34 was tested by intracerebral inoculation. Results: NG34 replicates in GBM cells in vitro with similar kinetics as those exhibited by an oHSV that is currently in clinical trials (rQNestin34.5). Dose–response cytotoxicity of NG34 in human GBM panels was equivalent to or improved compared with rQNestin34.5. The in vivo efficacy of NG34 against two human orthotopic GBM models in athymic mice was similar to that of rQNestin34.5, whereas intracerebral injection of NG34 in the brains of immunocompetent and athymic mice showed significantly better tolerability. NG34 was also effective in a syngeneic mouse glioblastoma model. Conclusions: A novel oHSV encoding GADD34 is efficacious and relatively nontoxic in mouse models of GBM. Clin Cancer Res; 24(11); 2574–84. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 5
    Publication Date: 2018-04-29
    Description: Objectives To explore the perceptions, attitudes, beliefs, and experiences related to Vietnamese medical students’ binge drinking. Design A qualitative study comprising semi-structured focus groups/interviews with medical students and semi-structured interviews with key informants. Thematic analysis of data. Setting Participants were a convenience sample of usual volunteers from a medical university in Viet Nam. Participants 19 medical students from year 1 to 6 and 4 key informants agreed to participate in the study. Results The study found participants believe medical students drink less than other students and are not binge drinkers yet they experience and/or witness many binge drinking occasions among medical students. Participants consider alcohol use as culturally acceptable in Vietnamese society and a way for medical students to create and improve relationships with their friends, teachers, or work colleagues. Group affiliation and peer pressure to drink excessive alcohol are identified among medical students, especially male students. Conclusion The culture of drinking behaviour was explored among medical students in Viet Nam. This study reveals a dichotomy between the belief of not being binge drinkers and the experience of many binge drinking occasions among medical students. This tension suggests future research about binge drinking behaviour of Vietnamese medical students is required.
    Keywords: Open access, Qualitative research
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 6
    Publication Date: 2018-03-27
    Description: Objectives To investigate recipient characteristics and rates of index angiography among First Nations (FN) and non-FN populations in Manitoba, Canada. Setting Population-based, secondary analysis of provincial administrative health data. Participants All adults 18 years or older who received an index angiogram between 2000/2001 and 2008/2009. Primary and secondary outcome measures (1) Descriptive statistics for age, sex, income quintile by rural and urban residency and Charlson Comorbidity Index for FN and non-FN recipients. (2) Annual index angiogram rates for FN and non-FN populations and among those rates of ‘urgent’ angiograms based on acute myocardial infarction (AMI)-related hospitalisations during the previous 7 days. (3) Proportions of people who did not receive an angiogram in the 20 years preceding an ischaemic heart disease (IHD) diagnosis or a cardiovascular death; stratified by age (〈65 or ≥65 years old). Results FN recipients were younger (56.3vs63.8 years; p〈0.0001) and had higher Charlson Comorbidity scores (1.32vs0.78; p〈0.001). During all years examined, index angiography rates were lower among FN people (2.67vs3.33 per 1000 population per year; p〈0.001) with no notable temporal trends. Among the index angiogram recipients, a higher proportion was associated with an AMI-related hospitalisation in the FN group (28.8%vs25.0%; p〈0.01) and in both groups rates significantly increased over time. FN people who died from cardiovascular disease or were older (65+years old) diagnosed with IHD were more likely to have received an angiogram in the preceding 20–30 years (17.8%vs12.5%; p〈0.01 and 50.9%vs49.5%; p〈0.03, respectively). FN people diagnosed with IHD who were under the age of 65 were less likely to have received an angiogram (47.8%vs53.1%; p〈0.01) Conclusions Index angiogram use differences are suggested between FN and non-FN populations, which may contribute to reported IHD disparities. Investigating factors driving these rates will determine any association between ethnicity and angiography services.
    Keywords: Open access, Cardiovascular medicine, Epidemiology
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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