Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebr...Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.展开更多
How to select a research topic that is appropriate for a clinician and that can lead to a peer-reviewed publication?In this essay,I will provide 5 tips:keep it interesting,keep it relevant,keep it inclusive,keep it si...How to select a research topic that is appropriate for a clinician and that can lead to a peer-reviewed publication?In this essay,I will provide 5 tips:keep it interesting,keep it relevant,keep it inclusive,keep it simple,and keep it trying.Keep it展开更多
In August of 2022,I gave the opening keynote address at the 5th North American Congress on Biomechanics,in Ottawa,Canada.The topic of my talk was about whether the research ecosystem was getting a reasonable return on...In August of 2022,I gave the opening keynote address at the 5th North American Congress on Biomechanics,in Ottawa,Canada.The topic of my talk was about whether the research ecosystem was getting a reasonable return on its investment in biomedical research.I provided several examples as to why I posed this question.展开更多
Monitoring of viral signal in wastewater is considered a useful tool for monitoring the burden of COVID-19,especially during times of limited availability in testing.Studies have shown that COVID-19 hospitalizations a...Monitoring of viral signal in wastewater is considered a useful tool for monitoring the burden of COVID-19,especially during times of limited availability in testing.Studies have shown that COVID-19 hospitalizations are highly correlated with wastewater viral signals and the increases in wastewater viral signals can provide an early warning for increasing hospital admissions.The association is likely nonlinear and time-varying.This project employs a distributed lag nonlinear model(DLNM)(Gasparrini et al.,2010)to study the nonlinear exposure-response delayed association of the COVID-19 hospitalizations and SARS-CoV-2 wastewater viral signals using relevant data from Ottawa,Canada.We consider up to a 15-day time lag from the average of SARS-CoV N1 and N2 gene concen-trations to COVID-19 hospitalizations.The expected reduction in hospitalization is adjusted for vaccination efforts.A correlation analysis of the data verifies that COVID-19 hospital-izations are highly correlated with wastewater viral signals with a time-varying rela-tionship.Our DLNM based analysis yields a reasonable estimate of COVID-19 hospitalizations and enhances our understanding of the association of COVID-19 hospi-talizations with wastewater viral signals.展开更多
"针刺临床试验干预措施报告标准"(STandards for Reporting Interventions in Clinical Trials of Acupuncture,STRICTA)于2001年和2002年在5种期刊上发表。该指南以对照检查清单及解释的形式供作者和期刊编辑使用,旨在提高..."针刺临床试验干预措施报告标准"(STandards for Reporting Interventions in Clinical Trials of Acupuncture,STRICTA)于2001年和2002年在5种期刊上发表。该指南以对照检查清单及解释的形式供作者和期刊编辑使用,旨在提高针刺临床试验报告的质量,尤其是对其中干预措施的报告,因而有助于对这些试验的解释和重复。随后对STRICTA的应用及影响的述评都强调了STRICTA的价值,也提出了改进和修订的建议。为使修订过程顺利进行,STRICTA工作组、CONSORT工作组和中国Cochrane中心于2008年开始合作。召集成立的有47名成员的专家组对清单的修改稿提出了电子版反馈意见。在后来于弗莱堡(Freiburg)召开的见面会上,由21名专家组成的工作组进一步修订了STRICTA对照检查清单,并计划如何对其进行发布。新的STRICTA对照检查清单作为CONSORT的正式扩展版,包含6项条目及17条二级条目。这些条目为报告针刺治疗的合理性、针刺的细节、治疗方案、其他干预措施、治疗师的背景以及对照或对照干预提供了指南。而且,作为修订工作的一部分,对每一条目作了详尽解释,并针对每一条目给出了报告良好的实例。此外,STRICTA中的"对照"(controlled)一词被替换成了"临床"(clinical),以示STRICTA适用于更广泛的各类临床评价设计,包括非对照结局研究和病例报道。修订的STRICTA对照检查清单有望与CONSORT声明及其非药物治疗扩展版一起共同提高针刺临床试验的报告质量。展开更多
Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases(RIPK) associated with the tumor necrosis factor-...Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases(RIPK) associated with the tumor necrosis factor-alpha(TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-α. However, subsequent lower doses(5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-α in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-α-induced necroptotic pathway after ischemic brain injury. Since Dabrafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.展开更多
CONSORT声明被广泛用于提高随机对照临床试验的报告质量。Kenneth Schulz等对CONSORT声明的最新版本CONSORT2010作了详细说明,该版本基于新获得的方法学证据和经验的积累对报告指南作了更新。为了鼓励更多的人使用"CONSORT2010声明...CONSORT声明被广泛用于提高随机对照临床试验的报告质量。Kenneth Schulz等对CONSORT声明的最新版本CONSORT2010作了详细说明,该版本基于新获得的方法学证据和经验的积累对报告指南作了更新。为了鼓励更多的人使用"CONSORT2010声明",本文可从bmj.com免费获取,也将在Lancet,Obstetrics and Gynecology,PLoS Medicine,Annals of Internal Medicine,Open Medicine,Journal of Clinical Epidemiology,BMC Medicine和Trials等杂志发表。展开更多
为了提高系统综述和荟萃分析文章报告的质量,2009年由国际著名专家组成的系统综述和荟萃分析优先报告的条目(Preferred Reporting Items for Systematic Reviews and Meta-Analyses,PRISMA)小组在国际重要医学期刊包括《英国医学杂志》...为了提高系统综述和荟萃分析文章报告的质量,2009年由国际著名专家组成的系统综述和荟萃分析优先报告的条目(Preferred Reporting Items for Systematic Reviews and Meta-Analyses,PRISMA)小组在国际重要医学期刊包括《英国医学杂志》、《临床流行病学杂志》、《内科学年鉴》和美国《公共科学图书馆医学杂志》等同步发表了《系统综述与荟萃分析优先报告条目:PRISMA声明》。该标准的制定对于改进和提高系统综述和荟萃分析的报告质量将起到重要作用。该声明较以往制定的《随机对照试验荟萃分析报告质量》(Quality of Reporting of Meta-Analyses),即《QUOROM声明》更加全面、完善。由于近年采国内外对系统综述的高度重视,发表的文章数量也越来越多,因此,有必要规范报告的标准,提高报告的质量。这份声明对系统综述和荟萃分析类文章报告的27个条目及流程图进行了定义和介绍,对相关条目进行了详细的解释和说明。及时向国内读者和临床试验研究人员介绍该声明具有重要的现实意义和学术价值。北京中医药大学循证医学中心刘建平等在第一时间内翻译了该声明,本刊希望通过介绍中文版《系统综述与荟萃分析优先报告的条目:PRISMA声明》,以进一步提高国内系统综述文章撰写和报告的质量,同时也有助于改进研究设计的方法学质量。本文的英文原文"Preferred reporring items for systematic reviews and meta-analyses:the PRISMAstatement"发表于PLoS Med.2009;6(7):e1000097.doi:10.1371/journal.pmed.1000097。该文中文版本由北京中医药大学循证医学中心李迅、曹卉娟翻译,刘建平审校(Tel:010-64286760;E-mail:jianping_l@hotmail.com)。中文译文的翻译出版由国家重点基础研究发展计划(973计划)项目资助(No.200608504602)。展开更多
Epithelial-mesenchymal transition(EMT) and mesenchymal-epithelial transition(MET) are essential for embryonic development and also important in cancer progression. In a conventional model, epithelial-like cancer cells...Epithelial-mesenchymal transition(EMT) and mesenchymal-epithelial transition(MET) are essential for embryonic development and also important in cancer progression. In a conventional model, epithelial-like cancer cells transit to mesenchymal-like tumor cells with great motility via EMT transcription factors; these mesenchymallike cells migrate through the circulation system, relocate to a suitable site and then convert back to an epithelial-like phenotype to regenerate the tumor. However, recent findings challenge this conventional model and support the existence of a stable hybrid epithelial/mesenchymal(E/M) tumor population. Hybrid E/M tumor cells exhibit both epithelial and mesenchymal properties, possess great metastatic and tumorigenic capacity and are associated with poorer patient prognosis. The hybrid E/M model and associated regulatory networks represent a conceptual change regarding tumor metastasis and organ colonization. It may lead to the development of novel treatment strategies to ultimately stop cancer progression and improve disease-free survival.展开更多
The prognosis of patients with metastatic liver disease remains dismal with a median survival of only 6-12 mo. As 80%-90% of patients are not candidates for surgical therapy, there is a need for effective non-surgical...The prognosis of patients with metastatic liver disease remains dismal with a median survival of only 6-12 mo. As 80%-90% of patients are not candidates for surgical therapy, there is a need for effective non-surgical therapies that would improve outcomes in these patients. The body of evidence related to the use of stereotactic ablative radiotherapy(SABR) in metastatic liver disease has substantially grown and evolved over the past decade. This review summarizes the current evidence supporting liver SABR with particular attention given to patient selection, target delineation, organ at risk dose volume constraints, response evaluation imaging and the various SABR techniques for delivering ablative radiotherapy to the liver. Even though it is unclear what dose-fractionation scheme, delivery system, concomitant therapy or patient selection strategy yields the optimum liver SABR outcomes, clear and growing evidence is available that SABR is a safe and effective therapy for the treatment of oligometastatic liver disease.展开更多
Ischemic brain injury triggers an inflammatory response. This response is necessary to clear damaged brain tissue but can also exacerbate brain injury. Microglia are the innate immune cells of the brain that execute t...Ischemic brain injury triggers an inflammatory response. This response is necessary to clear damaged brain tissue but can also exacerbate brain injury. Microglia are the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused synapses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.展开更多
Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on fun...Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.展开更多
Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyl...Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril tangles.Currently,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).展开更多
The objective of this guideline is to outline the role of magnetic resonance imaging(MRI) in clinical decision making and outcome prediction in patients with traumatic spinal cord injury(SCI).Methods A systematic revi...The objective of this guideline is to outline the role of magnetic resonance imaging(MRI) in clinical decision making and outcome prediction in patients with traumatic spinal cord injury(SCI).Methods A systematic review of the literature was conducted to address key questions related to the use of MRI in patients with traumatic SCI.This review focused on longitudinal studies that controlled for baseline neurologic status.A multidisciplinary Guideline Development Group(GDG) used this information,their clinical expertise,and patient input to develop recommendations on the use of MRI for SCI patients.Based on GRADE(Grading of Recommendation,Assessment,Development and Evaluation),a strong recommendation is worded as " we recommend," whereas a weaker recommendation is indicated by "we suggest." Results Based on the limited available evidence and the clinical expertise of the GDG,our recommendations were:(1) "We suggest that MRI be performed in adult patients with acute SCI prior to surgical intervention,when feasible,to facilitate improved clinical decision-making"(quality of evidence,very low) and(2) "We suggest that MRI should be performed in adult patients in the acute period following SCI,before or after surgical intervention,to improve prediction of neurologic outcome "(quality of evidence,low).Conclusions These guidelines should be implemented into clinical practice to improve outcomes and prognostication for patients with SCI.展开更多
Transparent reports of randomized trials occupy a central position in the delivery of evidence-based medicine;they can be used in systematic reviews and meta-analyses and,in turn,these reviews are often the starting p...Transparent reports of randomized trials occupy a central position in the delivery of evidence-based medicine;they can be used in systematic reviews and meta-analyses and,in turn,these reviews are often the starting point for appropriately developed practice guidance for clinicians.The most useful trial reports are those that are transparent,namely,the design and conduct is accurately and completely reported.Such reports enable readers to understand how the trial was conducted and therefore interpret the results.Reports that fail to meet this criterion are problematic for everybody — readers are left with an incomplete picture of what was done.As such,they are not able to judge the reliability and validity of the results and interpret them.Inadequate reporting is also problematic for those who participate in trials in the hope that their contributions will be of use to future patients;it diminishes this possibility.展开更多
Background: Guidelines for patients treated with conventional hemodialysis patients have been written for target serum levels for calcium (Ca), phosphate (PO4) and intact parathyroid hormone (iPTH). No guidelines exis...Background: Guidelines for patients treated with conventional hemodialysis patients have been written for target serum levels for calcium (Ca), phosphate (PO4) and intact parathyroid hormone (iPTH). No guidelines exist for nocturnal home hemodialysis (NHHD) patients for target values or timing of the blood sample draw. We undertook a prospective cohort study to examine the variability in pre, post and clinic (post-post) serum values for Ca, PO4, and iPTH in NHHD patients to determine if timing of blood draw could affect clinical decisions. Methods: Twenty prevalent NHHD patients collected blood pre and post their usual NHHD session with an additional blood sample drawn in clinic (post-post). Median and interquartile range of pre, post and clinic (post-post) values of iPTH, PO4 and Ca were calculated and compared with Freidman/Wilcoxon test. Serum concentrations were also categorized according to Canadian Society of Nephrology (CSN) guidelines target values for pre and clinic (post-post) samples. The proportion of patients that would be categorized differently by clinic (post-post) samples was determined. Results: There was a significant difference between pre-serum values compared to post and clinic (post-post) values. Overall, iPTH, PO4 and Ca values would be misclassified in 25%, 70% and 50% respectively if blood was drawn at the clinic visit (post-post) compared to pre-HD as per CSN guidelines. Conclusions: Although no specific guideline has been written for NHHD patients, to ensure consistency of management compared to in-centre HD patients, lab values should be drawn pre-HD until clinical evidence suggests that the recommendations should be different for NHHD.展开更多
文摘Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.
文摘How to select a research topic that is appropriate for a clinician and that can lead to a peer-reviewed publication?In this essay,I will provide 5 tips:keep it interesting,keep it relevant,keep it inclusive,keep it simple,and keep it trying.Keep it
文摘In August of 2022,I gave the opening keynote address at the 5th North American Congress on Biomechanics,in Ottawa,Canada.The topic of my talk was about whether the research ecosystem was getting a reasonable return on its investment in biomedical research.I provided several examples as to why I posed this question.
基金supported by the Natural Sciences and Engineering Research Council of Canada(NSERC EIDM)。
文摘Monitoring of viral signal in wastewater is considered a useful tool for monitoring the burden of COVID-19,especially during times of limited availability in testing.Studies have shown that COVID-19 hospitalizations are highly correlated with wastewater viral signals and the increases in wastewater viral signals can provide an early warning for increasing hospital admissions.The association is likely nonlinear and time-varying.This project employs a distributed lag nonlinear model(DLNM)(Gasparrini et al.,2010)to study the nonlinear exposure-response delayed association of the COVID-19 hospitalizations and SARS-CoV-2 wastewater viral signals using relevant data from Ottawa,Canada.We consider up to a 15-day time lag from the average of SARS-CoV N1 and N2 gene concen-trations to COVID-19 hospitalizations.The expected reduction in hospitalization is adjusted for vaccination efforts.A correlation analysis of the data verifies that COVID-19 hospital-izations are highly correlated with wastewater viral signals with a time-varying rela-tionship.Our DLNM based analysis yields a reasonable estimate of COVID-19 hospitalizations and enhances our understanding of the association of COVID-19 hospi-talizations with wastewater viral signals.
基金White RoseHealth Innovation Partnership Enterprise and Innovation Office+7 种基金 Charles Thackrah Building 101 Clarendon RoadLeeds LS2 9LJLeeds UK提供资金支持UK National Institute for Health Research的一项Career Scientist Award资助Cancer Research UK资助University of Ottawa Research Chair资助
文摘"针刺临床试验干预措施报告标准"(STandards for Reporting Interventions in Clinical Trials of Acupuncture,STRICTA)于2001年和2002年在5种期刊上发表。该指南以对照检查清单及解释的形式供作者和期刊编辑使用,旨在提高针刺临床试验报告的质量,尤其是对其中干预措施的报告,因而有助于对这些试验的解释和重复。随后对STRICTA的应用及影响的述评都强调了STRICTA的价值,也提出了改进和修订的建议。为使修订过程顺利进行,STRICTA工作组、CONSORT工作组和中国Cochrane中心于2008年开始合作。召集成立的有47名成员的专家组对清单的修改稿提出了电子版反馈意见。在后来于弗莱堡(Freiburg)召开的见面会上,由21名专家组成的工作组进一步修订了STRICTA对照检查清单,并计划如何对其进行发布。新的STRICTA对照检查清单作为CONSORT的正式扩展版,包含6项条目及17条二级条目。这些条目为报告针刺治疗的合理性、针刺的细节、治疗方案、其他干预措施、治疗师的背景以及对照或对照干预提供了指南。而且,作为修订工作的一部分,对每一条目作了详尽解释,并针对每一条目给出了报告良好的实例。此外,STRICTA中的"对照"(controlled)一词被替换成了"临床"(clinical),以示STRICTA适用于更广泛的各类临床评价设计,包括非对照结局研究和病例报道。修订的STRICTA对照检查清单有望与CONSORT声明及其非药物治疗扩展版一起共同提高针刺临床试验的报告质量。
基金supported by grants from the Heart and Stroke Foundation of Canada(HHC,AFRS)the Canadian Institutes of Health Research(to HHC and AFRS)supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario
文摘Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases(RIPK) associated with the tumor necrosis factor-alpha(TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-α. However, subsequent lower doses(5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-α in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-α-induced necroptotic pathway after ischemic brain injury. Since Dabrafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
文摘CONSORT声明被广泛用于提高随机对照临床试验的报告质量。Kenneth Schulz等对CONSORT声明的最新版本CONSORT2010作了详细说明,该版本基于新获得的方法学证据和经验的积累对报告指南作了更新。为了鼓励更多的人使用"CONSORT2010声明",本文可从bmj.com免费获取,也将在Lancet,Obstetrics and Gynecology,PLoS Medicine,Annals of Internal Medicine,Open Medicine,Journal of Clinical Epidemiology,BMC Medicine和Trials等杂志发表。
基金United Kingdom National Institute for Health ResearchCanadian Institutes of Health Research+4 种基金Presidents FundCanadian Institutes of Health ResearchJohnson & JohnsonBMJthe American Society for Clinical Oncology
文摘大量证据显示随机对照临床试验(randomised controlled trial,RCT)的报告质量不理想。报告不透明,则读者既不能评判试验结果是否真实可靠,也不能从中提取可用于系统综述的信息。最近的方法学分析表明,报告不充分和设计不合理与对治疗效果产生评价偏倚有关。这种系统误差对RCT损害严重,而RCT正是以其能减少或避免偏倚而被视为评价干预措施的金标准。为了提高RCT的报告质量,一个由专家和编辑组成的工作组制定了临床试验报告的统一标准(Consolidated Standards of Reporting Trials,CONSORT)声明。CONSORT声明于1996年首次发表,并于2001年更新。声明由对照检查清单和流程图组成,供作者在报告RCT时使用。许多核心医学期刊和主要国际性编辑组织都已认可CONSORT声明。该声明促进了对RCT的严格评价和解释。2001年,在对CONSORT进行修订时,人们就已经清楚地认识到,解释和说明制定CONSORT声明的原理,有助于研究人员等撰写或评价临床试验报告。一篇CONSORT说明与详述文章于2001年同2001版CONSORT声明一起发表。2007年1月的专家会议之后,对CONSORT声明作了进一步修订并已发表,即"CONSORT2010声明"。这次更新对原版对照检查清单作了文字上的修改,使其更为明晰,并收入了与一些新近才认识到的主题相关的建议,如选择性报告结局产生的偏倚。说明与详述文件旨在加强人们对CONSORT声明的理解、应用和传播,这次也作了大量修订,对每一项新增或更新的清单条目的含义和增改理由进行了解释,提供了优秀的报告实例,还尽可能地提供了相关的经验性研究的参考文献。文中收入了若干流程图实例。"CONSORT2010声明"、其说明与详述文件,以及相关网站(www.consort-statement.org),对于改进随机临床试验报告必将有所裨益。
文摘为了提高系统综述和荟萃分析文章报告的质量,2009年由国际著名专家组成的系统综述和荟萃分析优先报告的条目(Preferred Reporting Items for Systematic Reviews and Meta-Analyses,PRISMA)小组在国际重要医学期刊包括《英国医学杂志》、《临床流行病学杂志》、《内科学年鉴》和美国《公共科学图书馆医学杂志》等同步发表了《系统综述与荟萃分析优先报告条目:PRISMA声明》。该标准的制定对于改进和提高系统综述和荟萃分析的报告质量将起到重要作用。该声明较以往制定的《随机对照试验荟萃分析报告质量》(Quality of Reporting of Meta-Analyses),即《QUOROM声明》更加全面、完善。由于近年采国内外对系统综述的高度重视,发表的文章数量也越来越多,因此,有必要规范报告的标准,提高报告的质量。这份声明对系统综述和荟萃分析类文章报告的27个条目及流程图进行了定义和介绍,对相关条目进行了详细的解释和说明。及时向国内读者和临床试验研究人员介绍该声明具有重要的现实意义和学术价值。北京中医药大学循证医学中心刘建平等在第一时间内翻译了该声明,本刊希望通过介绍中文版《系统综述与荟萃分析优先报告的条目:PRISMA声明》,以进一步提高国内系统综述文章撰写和报告的质量,同时也有助于改进研究设计的方法学质量。本文的英文原文"Preferred reporring items for systematic reviews and meta-analyses:the PRISMAstatement"发表于PLoS Med.2009;6(7):e1000097.doi:10.1371/journal.pmed.1000097。该文中文版本由北京中医药大学循证医学中心李迅、曹卉娟翻译,刘建平审校(Tel:010-64286760;E-mail:jianping_l@hotmail.com)。中文译文的翻译出版由国家重点基础研究发展计划(973计划)项目资助(No.200608504602)。
基金supported by operating grants from Canadian Breast Cancer Foundation-Ontario Regionthe Canadian Institutes of Health Research MOP111224 to LW
文摘Epithelial-mesenchymal transition(EMT) and mesenchymal-epithelial transition(MET) are essential for embryonic development and also important in cancer progression. In a conventional model, epithelial-like cancer cells transit to mesenchymal-like tumor cells with great motility via EMT transcription factors; these mesenchymallike cells migrate through the circulation system, relocate to a suitable site and then convert back to an epithelial-like phenotype to regenerate the tumor. However, recent findings challenge this conventional model and support the existence of a stable hybrid epithelial/mesenchymal(E/M) tumor population. Hybrid E/M tumor cells exhibit both epithelial and mesenchymal properties, possess great metastatic and tumorigenic capacity and are associated with poorer patient prognosis. The hybrid E/M model and associated regulatory networks represent a conceptual change regarding tumor metastasis and organ colonization. It may lead to the development of novel treatment strategies to ultimately stop cancer progression and improve disease-free survival.
基金Supported by The Ottawa Hospital Foundationthe Ethel Ward Cushing Legacy Endowment Fund for a stereotactic ablative radiotherapy fellowship
文摘The prognosis of patients with metastatic liver disease remains dismal with a median survival of only 6-12 mo. As 80%-90% of patients are not candidates for surgical therapy, there is a need for effective non-surgical therapies that would improve outcomes in these patients. The body of evidence related to the use of stereotactic ablative radiotherapy(SABR) in metastatic liver disease has substantially grown and evolved over the past decade. This review summarizes the current evidence supporting liver SABR with particular attention given to patient selection, target delineation, organ at risk dose volume constraints, response evaluation imaging and the various SABR techniques for delivering ablative radiotherapy to the liver. Even though it is unclear what dose-fractionation scheme, delivery system, concomitant therapy or patient selection strategy yields the optimum liver SABR outcomes, clear and growing evidence is available that SABR is a safe and effective therapy for the treatment of oligometastatic liver disease.
基金supported by a grant from the Heart and Stroke Foundation of Canada(HHC,AFRS)a grant from the Natural Science&Engineering Research Council of Canada(HHC,AFRS)a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario,Canada(HHC)
文摘Ischemic brain injury triggers an inflammatory response. This response is necessary to clear damaged brain tissue but can also exacerbate brain injury. Microglia are the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused synapses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.
基金This work was supported by grants from the Heart and Stroke Foundation of Canada(Nos.G-13-0002596&G-18-0022157,to HHCNo.G-16-00014085,to AFRS)+2 种基金the Natural Science and Engineering Research Council of Canada(No.RGPIN/06212-2014,to HHC,No.RGPIN/2016-04985,to AFRS)the Canadian Institutes of Health Research(No.201610PJT,to HHC)HHC is also supported by a Mid-Career Investigator Award(No.7506)from the Heart and Stroke Foundation of Ontario.How to cite this article:Cruz SA。
文摘Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.
基金This work was supported by Ottawa Hospital Foundation,Scottish Rite Charitable Foundation research grant,NSERC and CIHR project grant(to JW).
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril tangles.Currently,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).
文摘The objective of this guideline is to outline the role of magnetic resonance imaging(MRI) in clinical decision making and outcome prediction in patients with traumatic spinal cord injury(SCI).Methods A systematic review of the literature was conducted to address key questions related to the use of MRI in patients with traumatic SCI.This review focused on longitudinal studies that controlled for baseline neurologic status.A multidisciplinary Guideline Development Group(GDG) used this information,their clinical expertise,and patient input to develop recommendations on the use of MRI for SCI patients.Based on GRADE(Grading of Recommendation,Assessment,Development and Evaluation),a strong recommendation is worded as " we recommend," whereas a weaker recommendation is indicated by "we suggest." Results Based on the limited available evidence and the clinical expertise of the GDG,our recommendations were:(1) "We suggest that MRI be performed in adult patients with acute SCI prior to surgical intervention,when feasible,to facilitate improved clinical decision-making"(quality of evidence,very low) and(2) "We suggest that MRI should be performed in adult patients in the acute period following SCI,before or after surgical intervention,to improve prediction of neurologic outcome "(quality of evidence,low).Conclusions These guidelines should be implemented into clinical practice to improve outcomes and prognostication for patients with SCI.
文摘Transparent reports of randomized trials occupy a central position in the delivery of evidence-based medicine;they can be used in systematic reviews and meta-analyses and,in turn,these reviews are often the starting point for appropriately developed practice guidance for clinicians.The most useful trial reports are those that are transparent,namely,the design and conduct is accurately and completely reported.Such reports enable readers to understand how the trial was conducted and therefore interpret the results.Reports that fail to meet this criterion are problematic for everybody — readers are left with an incomplete picture of what was done.As such,they are not able to judge the reliability and validity of the results and interpret them.Inadequate reporting is also problematic for those who participate in trials in the hope that their contributions will be of use to future patients;it diminishes this possibility.
文摘Background: Guidelines for patients treated with conventional hemodialysis patients have been written for target serum levels for calcium (Ca), phosphate (PO4) and intact parathyroid hormone (iPTH). No guidelines exist for nocturnal home hemodialysis (NHHD) patients for target values or timing of the blood sample draw. We undertook a prospective cohort study to examine the variability in pre, post and clinic (post-post) serum values for Ca, PO4, and iPTH in NHHD patients to determine if timing of blood draw could affect clinical decisions. Methods: Twenty prevalent NHHD patients collected blood pre and post their usual NHHD session with an additional blood sample drawn in clinic (post-post). Median and interquartile range of pre, post and clinic (post-post) values of iPTH, PO4 and Ca were calculated and compared with Freidman/Wilcoxon test. Serum concentrations were also categorized according to Canadian Society of Nephrology (CSN) guidelines target values for pre and clinic (post-post) samples. The proportion of patients that would be categorized differently by clinic (post-post) samples was determined. Results: There was a significant difference between pre-serum values compared to post and clinic (post-post) values. Overall, iPTH, PO4 and Ca values would be misclassified in 25%, 70% and 50% respectively if blood was drawn at the clinic visit (post-post) compared to pre-HD as per CSN guidelines. Conclusions: Although no specific guideline has been written for NHHD patients, to ensure consistency of management compared to in-centre HD patients, lab values should be drawn pre-HD until clinical evidence suggests that the recommendations should be different for NHHD.
