New hope for hepatitis C virus:Summary of global epidemiologic changes and novel innovations over 20 years

Hepatitis C virus(HCV)is a global health concern associated with significant morbidity and mortality.Before the approval of second-generation direct-acting antiviral agents(DAAs),interferon therapy and liver transplantation constituted the mainstay of treatment.The introduction of well-tolerated oral DAAs in late 2013 has revolutionized HCV management with over 95%cure rates.The predominance of HCV-related liver transplantations has declined following the widespread approval of DAAs.Despite the unparallel efficacy observed among these novel therapies,pharmaceutical costs continue to limit equitable access to healthcare and likely contribute to the differential HCV infection rates observed globally.To reduce the burden of disease worldwide,essential agenda items for all countries must include the prioritization of integrated care models and access to DAAs therapies.Through transparent negotiations with the pharmaceutical industry,the consideration for compassionate release of medications to promote equitable division of care is paramount.Here we provide a literature review of HCV,changes in epidemiologic trends,access issues for current therapies,and global inequities in disease burden.

Relapse of both small cell lung cancer and Lambert-Eaton myasthenic syndrome after a 13-year disease-free survival period

Lambert-Eaton myasthenic syndrome(LEMS) is a paraneoplastic syndrome and only 3%of small cell lung carcinoma(SCLC) patients have LEMS.Moreover,the recurrence of SCLC after a disease-free survival(DFS) of more than 10 years is rare.We report a patient who had a recurrence of both SCLC and LEMS after a 13-year DFS period.A 69-year-old man was diagnosed with LEMS and SCLC(cT0N2M0,stage ⅢA) 13 years ago.Chemoradiotherapy was performed and a complete response was achieved.With anticancer treatment,the LEMS symptoms was alleviated.At the age of 82 years,gait disturbance appeared followed by left supraclavicular lymphadenopathy and further examination revealed the recurrence of SCLC.Careful screening for the recurrence of SCLC might be needed when the patient has recurrent or secondary paraneoplastic neurological syndrome even after a long DFS period.

Humane Non-Human Primate Model of Traumatic Spinal Cord Injury Utilizing Electromyography as a Measure of Impairment and Recovery

The overall goal of this project is to develop a humane non-human primate model of traumatic spinal cord injury that will facilitate the development and evaluation of therapeutic interventions. The model utilizes neurophysiological techniques to identify the location of the upper motor neuron axons that innervate the lower motor neurons that control tail musculature. This facilitates the placement of a selective lesion that partially disconnects the upper and lower motor neuron supply to the musculature of the tail. An implanted transmitter quantitatively measures electromyography data from the tail. The preliminary data indicates that this model is feasible. The subject was able to tolerate the implantation of the transmitter, without adverse effects. As well, there was no limb impairment, bowel dysfunction or bladder dysfunction. The histopathologic and electromyographic features of the selective experimental lesion were similar to human spinal cord injury.

Childhood Exposure to Air Pollution as a Potential Contributor of Chronic Non-Respiratory Inflammatory Disorders: A Longitudinal Prospective Cohort Study in Hamilton, Canada

This study examines the relationship between childhood exposure to air pollution and diagnosis with chronic non-respiratory health outcomes in adulthood. This prospective cohort study uses data collected in the 1970/1980s from 395 children, including exposure to air pollution. Over thirty years later, a survey collected data on various health outcomes, including diagnosis with arthritis, high blood pressure, long-term skin conditions, and hay fever allergies. Logistic regression modeling was performed to examine the relative contribution of childhood exposure to air pollution on chronic non-respiratory health outcomes in adulthood. Childhood exposure to SO2 emerged as a significant predictor of arthritis (OR = 2.73, 95% CI 1.20 - 6.18) and high blood pressure (OR = 2.82, 95% CI 1.23 - 6.47). Other significant predictors include respiratory symptoms during childhood, family income during childhood and adulthood, property tenure, employment status, residential exposures, life events, physical activity, and body mass index. Childhood exposure to air pollution did not emerge as a significant predictor of long-term skin conditions or hay fever allergies. Findings contribute to the debate on the health effects of air pollution, indicating that the health impacts of childhood exposure to air pollution may include chronic inflammatory disorders in adulthood.

Humane Non-Human Primate Model of Traumatic Spinal Cord Injury: Quantitative Analysis of Electromyographic Data

A valid non human primate model of traumatic spinal cord injury (TSCI) is essential to evaluate and develop new treatments. In previous experiments, it has been demonstrated that a transmitter can be implanted in the macaque fasicularis monkey that measures electromyographic data from the musculature of the tail. As well, previous experiments have demonstrated that selective lesions can be created in the lower thoracic spinal cord that does not cause limb weakness and/or bowel dysfunction. The histopathological features of these lesions appear similar to human TSCI. This paper describes a method by which the EMG data can be transformed into a quantitative metric of volitional limb movement (“Q”). This metric permits an objective assessment of injury, natural recovery as well as potential efficacy of candidate treatments.

Health-related quality-of-life and health-utility reporting in critical care

Mortality is a well-established patient-important outcome in critical care studies.In contrast,morbidity is less uniformly reported(given the myriad of critical care illnesses and complications of each)but may have a common end-impact on a patient’s functional capacity and health-related quality-of-life(HRQoL).Survival with a poor quality-of-life may not be acceptable depending on individual patient values and preferences.Hence,as mortality decreases within critical care,it becomes increasingly important to measure intensive care unit(ICU)survivor HRQoL.HRQoL measurements with a preference-based scoring algorithm can be converted into health utilities on a scale anchored at 0(representing death)and 1(representing full health).They can be combined with survival to calculate quality-adjusted life-years(QALY),which are one of the most widely used methods of combining morbidity and mortality into a composite outcome.Although QALYs have been use for health-technology assessment decision-making,an emerging and novel role would be to inform clinical decision-making for patients,families and healthcare providers about what expected HRQoL may be during and after ICU care.Critical care randomized control trials(RCTs)have not routinely measured or reported HRQoL(until more recently),likely due to incapacity of some patients to participate in patient-reported outcome measures.Further differences in HRQoL measurement tools can lead to non-comparable values.To this end,we propose the validation of a gold-standard HRQoL tool in critical care,specifically the EQ-5D-5L.Both combined health-utility and mortality(disaggregated)and QALYs(aggregated)can be reported,with disaggregation allowing for determination of which components are the main drivers of the QALY outcome.Increased use of HRQoL,health-utility,and QALYs in critical care RCTs has the potential to:(1)Increase the likelihood of finding important effects if they exist;(2)improve research efficiency;and(3)help inform optimal management of critically ill patients allowing for decision-making about their HRQoL,in additional to traditional health-technology assessments.

紫杉醇诱导犬乳腺肿瘤细胞凋亡和细胞ROS及SOD失衡的研究

为研究紫杉醇诱导犬乳腺肿瘤细胞(CHMm)凋亡及对氧化还原平衡的影响,本实验以不同浓度的紫杉醇处理细胞,采用台盼蓝排斥试验和MTT法检测细胞活性,并进行丫啶橙(AO)/溴化乙锭(EB)双荧光染色以及在透射电镜下观察CHMm细胞凋亡和形态学变化,并检测细胞内活性氧(ROS)、超氧化物岐化酶(SOD)、过氧化氢酶(CAT)和丙二醛(MDA)等反映细胞内氧化还原功能的指标。结果显示:在紫杉醇的作用下,CHMm生长受到不同程度的抑制,引起细胞凋亡,出现典型的凋亡形态;ROS和MDA含量增加,SOD和CAT酶活性降低,细胞内出现氧化还原失衡。表明紫杉醇能够抑制CHMm细胞生长,打破氧化还原平衡,诱导细胞凋亡并呈浓度和时间依赖性。

p27在大鼠肾间质纤维化中的表达及依那普利对其干预后的影响

目的:研究单侧输尿管梗阻(unilateralureteralobstruction,UUO)大鼠肾小管上皮细胞p27的表达与肾间质纤维化的关系,并探讨血管紧张素转化酶抑制剂依那普利干预后p27表达的变化,以进一步阐述其抗纤维化机制。方法:90只SD大鼠随机分成假手术组(sham-operatedrates,SOR)、UUO模型组、依那普利治疗组(UUO+Enalapariltreatedgroup,T-UUO)。于术后第7,14,21天分别处死各组大鼠10只。用HE染色动态观察肾脏病理变化,免疫组织化学法测定p27的表达及动态变化,RT-PCR法测定p27mRNA的水平。结果:SOR组肾小管上皮细胞p27蛋白及肾皮质p27mRNA的表达均强,UUO组随着间质纤维化程度的加重,p27mRNA的表达逐渐减弱,而依那普利在UUO术后第14,21天能增强p27的表达。结论:(1)p27参与了UUO大鼠肾间质纤维化的发病过程;(2)UUO大鼠肾间质纤维化模型中依那普利抗间质纤维化机制部分是通过增强p27的表达。

提高实效性临床试验报告的质量——《CONSORT声明》的扩展

近年来实效性临床试验受到更多重视,尤其在传统医学临床评价研究领域。为了提高实效性临床试验报告的质量,CONSORT声明组和医疗保健体系中的实效性随机对照临床试验(pragmatic randomized controlled trials in health care systems,PRACTIHC)小组对《CONSORT声明》进行了修改,以帮助读者评估试验质量和结果的可靠性。实效性试验报告指南,作为《CONSORT声明》的一个特殊扩展,能在报告、评价和应用实效性试验方面帮助编辑、系统评价者、试验设计者和决策者评估实效性试验报告中的信息,判定其结论是否适用,以及干预措施是否可行、可否被接受。2005年1月和2008年3月,在加拿大多伦多分别举行了为期两天的会议来探讨提高随机对照试验对卫生保健决策贡献的方法,焦点集中于实效性试验。2005年会,后扩展版草案修订清单发送至编写组成员,经过几次修订,编写组起草了一份摘要草案。在2008年讨论并修改了这一草案。这份草案发给CONSORT声明组以供修改并发表。这份声明的扩展版提出了对8个条目的补充。及时向国内读者和临床试验研究人员介绍该指南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教授等在短时间内翻译了该指南。本刊希望通过介绍中文版"提高实效性临床试验报告的质量——《CONSORT声明》的扩展"以提高国内实效性临床试验报告的质量,相信也有助于改进试验设计的方法学质量。

临床推荐意见分级标准的认可

过去十年，临床实践指南质量的持续改善和提高得益于采纳了一些基本原则，如根据相关证据生产的系统评价对推荐意见和潜在证据的质量分级。但由此而产生的大量证据与推荐意见分级标准系统相互矛盾，让人困惑。

An Emerging Consensus on Grading Recommendations?

Clinical practice guidelines:The challenge of grading Clinical practice guidelines have improved in quality over the past ten years by adhering to a few basic principles,such as conducting thorough systematic reviews of relevant evidence,and grading the recommendations and the quality of the underlying evidence．The large number of systems of measuring the quality of evidence and recommendations that have emerged are,however,confusing．An international group of guideline developers, systematic reviewers,and clinical

比较胺碘酮加β受体阻断剂、单用索他洛尔与单用β受体阻断剂预防埋藏式复律除颤器电击的随机试验:OPTIC研究

Context: Implantable cardioverter defibrillator(ICD) therapy is effective but is associated with high-voltage shocks that are painful. Objective: To determine whether amiodarone plus β -blocker or sotalol are better than β -blocker alone for prevention of ICD shocks. Design, Setting, and Patients: A randomized controlled trial with blinded adjudication of events of 412 patients from 39 outpatient ICD clinical centers located in Canada, Germany, United States, England, Sweden, and Austria, conducted from January 13, 2001, to September 28, 2004. Patients were eligible if they had received an ICD within 21 days for inducible or spontaneously occurring ventricular tachycardia or fibrillation. Intervention: Patients were randomized to treatment for 1 year with amiodarone plus β -blocker, sotalol alone, or β -blocker alone. Main Outcome Measure: Primary outcome was ICD shock for any reason. Results: Shocks occurred in 41 patients(38.5% ) assigned to β -blocker alone, 26(24.3% ) assigned to sotalol, and 12(10.3% ) assigned to amiodarone plus β -blocker. A reduction in the risk of shock was observed with use of either amiodarone plus β -blocker or sotalol vs β -blocker alone(hazard ratio[HR], 0.44; 95% confidence interval[CI], 0.28- 0.68; P< .001). Amiodarone plus β -blocker significantly reduced the risk of shock compared with β -blocker alone(HR, 0.27; 95% CI, 0.14- 0.52; P< .001) and sotalol(HR, 0.43; 95% CI, 0.22- 0.85; P=.02). There was a trend for sotalol to reduce shocks compared with β -blocker alone(HR, 0.61; 95% CI, 0.37- 1.01; P=.055). The rates of study drug discontinuation at 1 year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for β -blocker alone. Adverse pulmonary and thyroid events and symptomatic bradycardia were more common among patients randomized to amiodarone. Conclusions: Despite use of advanced ICD technology and treatment with a β -blocker, shocks occur commonly in the first year after ICD implant. Amiodarone plus β -blocker is effective for preventing these shocks and is more effective than sotalol but has an increased risk of drug-related adverse effects. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT00257959.

Key questions resulting from the JUPITER trial assessing cardiovascular disease intervention with rosuvastatin

This paper presents an analysis of the recently published Justification for the Use of statins in Prevention(JUPITER:an intervention trial evaluating rosuvastatin) trial,which tested the statin rosuvastatin in apparently healthy individuals with no prior cardiovascular(CVD) disease and with normal plasma low density lipoprotein(LDL) cholesterol concentrations but with raised plasma high sensitivity C-reactive protein(hsCRP) levels.The rate of the combined primary CVD endpoint was significantly reduced in the treatment arm after a median of under 2 years.The JUPITER trial is distinct from previous studies examining statin use in primary prevention groups because the target group for drug therapy was apparently healthy men and women at low or intermediate risk for developing CVD.On the basis of JUPITER's findings,there are key questions that should be assessed on the therapeutic intervention of CVD regarding:the primary prevention groups that should be targeted for statin therapy,the utility of targets in addition to plasma LDL cholesterol levels,and the need to consider the metabolic state of individuals targeted for therapy(including the presence of obesity and inflammation).The conclusion from the current analysis is that the JUPITER results warrant further LDL cholesterol lowering than is currently targeted in primary prevention groups that have a pre-existing condition or lifestyle that elevates CVD risk but still do not have a high global CVD risk(as assessed with current algorithms).This group is not captured in current widely used CVD risk calculations,however,with the identification of useful biomarkers,such as hsCRP,this group can be better identified and targeted for intervention.

成人肌营养不良患者的营养缺乏

Patients with muscular dystrophy may be prone to nutrient deficiency due to mo bility limitations or oropharyngeal weakness. Patients with myotonic muscular dy strophy (DM1) may be particularly prone to nutritional deficiencies from associa ted dysmotility of the entire gastrointestinal tract. We prospectively evaluated nutritional intake, body composition, and muscle strength in adult patients wit h DM1 (n=29) and other muscular dystrophies (n=22) on two occasions separated by ～6 months. Handgrip was significantly lower and knee extension higher for DM1 compared to other dystrophies, with no between-group differences in nutritional intakes. Many patients in both groups demonstrated inadequate nutrient intake o f protein, energy, vitamins (water and fat soluble), and minerals (calcium and m agnesium). Significant correlations were found between measures of strength and certain individual nutrients (e.g., copper and water-soluble vitamins). These d ata indicate that a substantial number of adults with muscular dystrophy do not meet current dietary intake recommendations. The potential clinical implications of these findings are discussed.

外周动脉疾病的药物治疗

背景：外周动脉疾病（peripheral arterial disease，PAD）见于大约20％的55岁以上成人，是心肌梗死、卒中和血管性死亡的有力预测因素。其治疗目标是预防主要冠状动脉和脑血管事件，改善下肢症状。 目的：对药物治疗PAD的最佳证据进行评估。 证据获取：检索MEDLINE和Cochrone数据库，对1990—2005年11月药物治疗PDA的随机试验进行汇总分析，同时检索这些文章的参考文献。检索词（单独和组合）包括：外周动脉病、外周动脉疾病、PAD、随机对照试验、对照试验、随机和汇总分析（metaanalysis）。特别关注PAD临床相关药物治疗的随机对照试验和汇总分析。预后评价指标包括腿部症状（间歇性跛行和行走距离）、死亡以及主要冠状动脉及脑血管事件。 证据综合：戒烟（医生建议、尼古丁替代治疗和bupropion）、系统锻炼计划、他汀类药物、西洛他唑（cilostazol）和血管紧张素转换酶抑制剂（ACE抑制剂）可改善间歇性跛行症状、行走距离和生活质量。使用ACE抑制剂和其他降压药物控制血压、服用他汀类药物、使用阿斯匹林或氯吡格雷进行抗血小板治疗、可能还有戒烟均可降低发生主要心脑血管事件的危险。 结论：改善生活方式（戒烟、锻炼）和药物治疗（尼古丁替代治疗、bupropion、降压药物、他汀类药物和抗血小板药物）可降低PAD不断增加的沉重负担，减少局部及全身并发症。

Evidence-based medicine and precision medicine:complementary approaches to clinical decision-making

Evidence-based medicine is widely promoted for decision-making in health care and is associated with improved patient outcomes.Critics have suggested that evidence-based medicine focuses primarily on groups of patients rather than individuals,but often fail to consider subgroup analyses,N-of-1 trials,and the incorporation of patient values and preferences.Precision medicine has been promoted as an approach to individualize diagnosis and treatment of diseases through genetic,biomarker,phenotypic,and psychosocial characteristics.However,there are often high costs associated with personalized medicine,and high-quality evidence is lacking for effectiveness in many applications.For the potential of personalized medicine to be realized,it must adhere to the principles of evidencebased medicine:(1)evidence in isolation is not sufficient to make clinical decisions—patient’s values and preferences as well as resource implications must be considered,and(2)there is a hierarchy of evidence to guide clinical decision-making and studies at lower risk of bias are likely to provide more trustworthy findings.

血浆置换和糖皮质激素治疗抗中性粒细胞胞质抗体相关性血管炎:临床实践指南

对于抗中性粒细胞胞质抗体(antineutrophil cytoplasmic antibody,ANCA)相关性血管炎(ANCA-associated vasculitis,AAV)患者,血浆置换的作用是什么?接受治疗前6个月糖皮质激素的最佳剂量是多少?一项新发表的随机对照试验(randomised controlled trial,RCT)引起本次指南的制订。

亚组效应可信吗？评估亚组分析可信度的最新标准

我们怎样才能区分亚组效应的真伪？本文提出了评价亚组分析可信度的新标准和一个参照表；

肠促胰素类药物治疗与2型糖尿病患者的死亡风险：系统性综述和meta分析

目的评价2型糖尿病患者使用肠促胰素类药物治疗对全因死亡的影响。设计随机对照试验（RCT）的系统性综述和meta分析。数据来源来自Medline、Embase、the Cochrane Central Register of Controlled Trials（CENTRAL）、Clinical Trials．gov。纳入标准2型糖尿病患者使用胰高血糖素样肽-1（GLP-1）受体激动剂或二肽基肽酶-4（DPP-4）抑制剂与使用安慰剂或其他降糖药物治疗相比的RCT。数据收集和分析2名研究者独立筛选文献，评价纳入研究的偏倚风险，并提取数据。采用Peto法作为合并来自RCT效应估计的主要方法，采用其他统计方法进行敏感性分析，针对6种预先设定的假设开展meta回归来探索异质性。使用GRADE方法评价证据质量。结果纳入189个RCT（n=155145），偏倚风险为低至中等。其中77个RCT报告零死亡事件，112个RCT报告在151614例患者中发生3888例死亡事件。meta分析结果显示：肠促胰素类药物与对照组相比，死亡风险在组间差异无统计学意义f1925／84136比1963／67478；比值比（OR）=0．96，95％可信区间（CI）：0．90-1．02，I^2=0％；率差（RD）=比对照低3／1000，95％C1（比对照低7／1000～比对照高1／1090）／5年·1000例患者；中等质量证据1。亚组分析结果提示：GLP-1受体激动剂可能降低死亡风险，但DPP-4抑制剂未发现类似结果；该亚组效应的可信度较低。敏感性分析结果未发现明显差异。结论当前证据不支持肠促胰素类药物增加2型糖尿病患者死亡风险的假设。需进一步研究证实GLP-1受体激动剂与DPP．4抑制剂两类肠促胰素类药物之间是否存在差异。

指南制定中专家意见与专家证据的区别

Holger J Schünemann及其同事表示,制定指南时,专家经验非常有用,但需要有明确的使用方法,以避免意见和证据的混淆。循证指南制定团队应该包括临床、公共卫生或其他相关领域的专家,团队具备对证据进行综合判断的能力。对做出一系列判断的依据——证据,进行识别、选择、评价和归纳的过程应以系统和透明的方式进行呈现。但针对证据可能尚未发表、间接证据、疾病罕见、背景信息缺失,或资源有限等情况,系统而透明地呈现证据则存在一定难度。在这种情况下,使用专家提供的证据是有效的,即专家可能是证据的唯一或主要来源。