Systematic reviews in health care Investigating and dealing with publication and other biases

systematical literature reviewSystematic Literature Reviews: A GuideSystematic literature review is a research method used to identify, appraise, and synthesize available evidence in a systematic and rigorous manner. This method is particularly useful when trying to answer a specific research question or to inform policy and practice.1. Defining the research questionThe first step in conducting a systematic literature review is to clearly define the research question. This step involves identifying the research topic and formulating research questions that are specific, clear, and relevant to the study aim. The research questions should guide the search process and help identify relevant studies.2. Conducting a comprehensive searchThe second step is to identify relevant studies by conducting a comprehensive search. This search involves searching multiple electronic databases, grey literature, conference proceedings, and other sources of information. Keywords, indexing terms, and inclusion and exclusioncriteria are used to guide the search process.3. Screening and selecting studiesThe third step is to screen and select studies that meet the inclusion and exclusion criteria. This involves reviewing the titles, abstracts, and full-texts of potential studies to determine their relevance to the research questions. The selected studies are then included in the review.4. Data extraction and appraisalThe fourth step is to extract data from the selected studies and appraise their quality. This involves collecting data on the study population, design, intervention, outcome measures, and results. The quality of the studies is assessed using predetermined criteria such as the Cochrane Risk of Bias tool.5. Synthesizing the evidenceThe fifth and final step is to synthesize the evidence by analyzing and summarizing the findings of the selected studies. This involves combining the results of individual studies to determine the overall effect size and strength of evidence. Meta-analysis, sub-group analysis, and narrative synthesis are some methods that can be used to synthesize the evidence.Systematic literature review is a rigorous and transparent method of synthesizing evidence that is useful in informing policy and practice. Its strength lies in itsability to identify, appraise, and synthesize a large body of evidence in a systematic and comprehensive manner.。

医疗器械专业英语In recent years, the field of medical device technology has seen significant advancements. With the increasing global demand for innovative and reliable medical devices, it is crucial for professionals in the industry to have a strong command of medical device-specific English terminology. This article aims to explore the importance of English proficiency in the medical device profession, provide an overview of key terms and concepts, and discuss the benefits of effective communication in this specialized field.I. IntroductionIn the ever-evolving landscape of healthcare, medical devices play a pivotal role in diagnosing, treating, and monitoring patients. Medical device professionals, from engineers to sales representatives, are required to communicate with colleagues, suppliers, and clients across the globe. English language proficiency has thus become an essential skill in this sector, as it allows effective collaboration and ensures safety and accuracy in product development, production, and distribution processes.II. Key Terminology in Medical Device IndustryA. Regulatory Standards and Compliance1. FDA Regulations: The Food and Drug Administration (FDA) is responsible for regulating medical devices in the United States. Understanding key terms such as "pre-market approval," "510(k) clearance," and "Good Manufacturing Practices (GMP)" is imperative for compliance with FDA regulations.2. International Standards: The International Organization for Standardization (ISO) provides industry-wide guidance and harmonization. Familiarity with ISO 13485 (Quality Management Systems - Medical Devices) and ISO 14971 (Risk Management for Medical Devices) is crucial for compliance in the global market.B. Product Development and Manufacturing1. Design Controls: These are systematic processes to manage the development of medical devices, ensuring that they meet the intended use, user needs, and regulatory requirements.2. Verification and Validation: These processes involve testing and confirming that a medical device meets the specifications and functions as intended.3. Quality Control: Quality control measures ensure that medical devices consistently meet defined quality standards.C. Post-Market Surveillance1. Adverse Events: These refer to unexpected or harmful incidents associated with the use of medical devices. Reporting and investigating adverse events play a crucial role in patient safety and maintaining regulatory compliance.2. Vigilance Reporting: Vigilance reporting involves the proactive identification and reporting of any potential risks or issues related to medical devices.III. Effective Communication in the Medical Device FieldA. Collaborative Product Development1. Design Reviews: Regular design reviews allow cross-functional teams to evaluate and provide feedback on the progress and quality of device development.2. Translations and Localization: As medical device companies expand globally, effective translation and localization of product information, labeling, and manuals are critical to ensure safe and accurate usage of devices in different markets.B. Sales and Marketing1. Product Presentations: Sales representatives must effectively communicate the features, benefits, and intended uses of medical devices to healthcare professionals and potential buyers.2. Technical Support: Timely and accurate technical support, via phone or email, helps healthcare providers resolve any issues related to the operation, maintenance, or troubleshooting of medical devices.IV. Benefits of English Proficiency in the Medical Device ProfessionA. Global Networking: English proficiency facilitates effective communication and collaboration with international partners, suppliers, and regulatory authorities, expanding the reach and impact of medical device companies.B. Career Advancement: A strong command of medical device-specific English terminology opens up career opportunities, allowing professionals towork on complex projects, participate in global conferences, and contribute to industry knowledge sharing.C. Enhanced Safety and Quality: Effective communication ensures that medical devices are developed, manufactured, and used in strict adherence to regulatory standards and industry best practices, ultimately promoting patient safety and product reliability.V. ConclusionIn the dynamic field of medical devices, English proficiency is a valuable asset that enables effective communication, compliance with global regulations, and overall advancement in the industry. Professionals in the medical device field should prioritize the development of their English skills to effectively and confidently navigate this complex and rewarding sector.。

A 安全性安全性 Safety B 半随机对照试验半随机对照试验 quasi- randomized control trial，qRCT 背景问题背景问题 background questions 比值比比值比 odds ratio ，OR 标准化均数差标准化均数差 standardized mean difference, SMD 病例报告病例报告 case report 病例分析病例分析 case analysis 病人价值观病人价值观 patient value （此词删除）（此词删除）病人预期事件发生率病人预期事件发生率 patient ’s expected event rate, PEER 补充替代医学补充替代医学 complementary and alternative medicine, CAM 不良事件不良事件 adverse event 不确定性不确定性 uncertainty C Cochrane 图书馆图书馆Cochrane Library, CL Cochrane 系统评价系统评价Cochrane systematic review, CSR Cochrane 协作网协作网Cochrane Collaboration, CCCox 比例风险模型比例风险模型Cox ’ proportional hazard model 参考试验偏倚参考试验偏倚 References test bias 肠激惹综合征 irritable bowel syndrome，IRB 肠激惹综合征测量变异 measurement variation 测量变异效果 cost-effectiveness 成本-效果效果分析 cost-effectiveness analysis 成本-效果分析效益分析 cost-benefit analysis 成本-效益分析效用分析 cost-utility analysis 成本-效用分析成本最小化分析（最小成本分析）cost-minimization analysis 重复发表偏倚 Multiple publication bias 重复发表偏倚传统医学 Traditional Medicine，TM 传统医学D D—L法DerSimonian & Laird method 发生一例不良反应所需治疗的病例数发生一例不良反应所需治疗的病例数，NNH the number needed to harm one more patients from the therapy对抗疗法 allopathic medicine，AM 对抗疗法对照组中某事件的发生率 control event rate，CER 对照组中某事件的发生率多重发表偏倚 multiple publication bias (删除此词) 多重发表偏倚E 二次研究 secondary studies 二次研究二次研究证据 secondary research evidence 二次研究证据F 发表偏倚 publication bias 发表偏倚例有利结果需要治疗的病例数防止1例不良事件发生或得到1例有利结果需要治疗的病例数number needed to treat，NNT 非随机同期对照试验 non-randomized concurrent control trial 非随机同期对照试验分层随机化 stratified randomization 分层随机化分类变量 categorical variable 分类变量风险（危险度） risk 风险（危险度）G 干扰 co-intervention 干扰工作偏倚 Workup bias 工作偏倚固定效应模型 fixed effect model 固定效应模型国际临床流行病学网 International Clinical Epidemiology Network, INCLEN 国际临床流行病学网H 灰色文献 grey literature 灰色文献后效评价 reevaluation 后效评价获益 benefit 获益J 机会结 chance node 机会结疾病谱偏倚 Spectrum bias 疾病谱偏倚技术特性 Technical properties 技术特性加权均数差 weighted mean difference, WMD 加权均数差假阳性率（误诊率） false positive rate 假阳性率（误诊率）假阴性率（漏诊率） false negative rate 假阴性率（漏诊率）简单随机化 simple randomization 简单随机化检索策略 search strategy 检索策略交叉对照研究（交叉设计） crossover design 交叉对照研究（交叉设计）经济学分析 economic analysis 经济学分析经济学特性 Economic attributes or impacts 经济学特性经验医学 empirical medicine 经验医学精确性 precision 精确性决策结 decision node 决策结决策树分析 decision tree analysis 决策树分析绝对获益增加率 absolute benefit increase, ABI 绝对获益增加率绝对危险度降低率 absolute risk reduction, ARR 绝对危险度降低率绝对危险度增加率 absolute risk increase, ARI 绝对危险度增加率K 可重复性 repeatability，reproducibility 可重复性可靠性（信度） reliability 可靠性（信度）可信区间 confidence interval ，CI 可信区间可信限 confidence limit ，CL 可信限L 回归模型 Logistic regression model Logistic回归模型历史性对照研究 historical control trial 历史性对照研究利弊比 likelihood of being helped vs harmed, LHH 利弊比连续性变量 continuous variable 连续性变量临床对照试验 controlled clinical trial, CCT临床对照试验临床结局 clinical outcome 临床结局临床经济学 clinical economics 临床经济学临床决策分析 clinical decision analysis 临床决策分析临床流行病学 clinical epidemiology, CE 临床流行病学临床实践指南 clinical practice guidelines, CPG 临床实践指南临床试验 clinical trial 临床试验临床研究证据 clinical research evidence 临床研究证据临床证据 clinical evidence 临床证据临床证据手册 handbook of clinical evidence 临床证据手册零点 Zero time 零点灵活性 flexibility 灵活性临界点 Cut off points 临界点漏斗图 funnel plots 漏斗图率差（或危险差） rate difference，risk difference，RD 率差（或危险差）M 分析 Meta-analysis Meta-分析敏感度 sensitivity 敏感度敏感性分析 sensitivity analysis 敏感性分析墨克手册 Merck manual 墨克手册N 脑卒中病房 Stroke Unit 脑卒中病房内在真实性 internal validity 内在真实性P 偏倚 bias 偏倚Q 起始队列 inception cohort 起始队列后对照研究 before-after study 前-后对照研究前景问题 foreground questions 前景问题区组随机化 block randomization 区组随机化S 散点图 scatter plots 散点图森林图 forest plots 森林图伤残调整寿命年 disability adjusted life year，DALY 伤残调整寿命年生存曲线 survival curves 生存曲线生存时间 survival time 生存时间生存质量（生活质量） quality of life 生存质量（生活质量）世界卫生组织 World Health Organization, WHO 世界卫生组织失安全数 fail-Safe Number 失安全数试验组某事件发生率 experimental event rate，EER 试验组某事件发生率似然比 likelihood Ratio, LR 似然比适用性 applicability 适用性受试者工作特征曲线（ROC曲线）receiver operator characteristic curve 随机对照临床试验 randomized clinical trials, RCT 随机对照临床试验随机对照试验 randomized control trial, RCT随机对照试验随机化隐藏 randomization concealment 随机化隐藏随机效应模型 random effect model 随机效应模型T 特异度 specificity 特异度同行评价 colleague evaluation 同行评价统计效能（把握度） power 统计效能（把握度）同质性检验 tests for homogeneity 同质性检验W 外在真实性 external validity 外在真实性完成治疗分析 per protocol，PP 完成治疗分析腕管综合征 carpal tunnel syndrome, CTS 腕管综合征卫生技术 health technology 卫生技术卫生技术评估 health technology assessment, HTA 卫生技术评估X 系统评价 systematic review, SR 系统评价相对获益增加率 relative benefit increase, RBI 相对获益增加率相对危险度 relative risk，RR 相对危险度相对危险度降低率 relative risk reduction, RRR 相对危险度降低率相对危险度增加率 relative risk increase, RRI 相对危险度增加率效果 effectiveness 效果效力 efficacy 效力效应尺度 effect magnitude 效应尺度效应量 effect size 效应量序贯试验 sequential trial 序贯试验选择性偏倚 selection bias 选择性偏倚循证儿科学 evidence-based pediatrics 循证儿科学循证妇产科学 evidence-based gynecology & obstetrics 循证妇产科学循证购买 evidence-based purchasing 循证购买循证护理 evidence-based nursing 循证护理循证决策 evidence-based decision-making 循证决策循证内科学 evidence-based internal medicine 循证内科学循证筛选 evidence-based selection 循证筛选循证外科学 evidence-based surgery 循证外科学循证卫生保健 evidence-based health care 循证卫生保健循证诊断 evidence-based diagnosis 循证诊断循证医学 evidence-based medicine, EBM 循证医学Y 亚组分析 subgroup analysis 亚组分析严格评价 critical appraisal 严格评价验后比 post-test odds 验后比验后概率 post-test probability 验后概率验前比 pre-test odds 验前比验前概率 pre-test probability 验前概率阳性预测值 positive predictive value 阳性预测值原始研究 primary studies 原始研究异质性检验 tests for heterogeneity 异质性检验意向治疗分析 intention-to-treat, ITT 意向治疗分析阴性预测值 negative predictive value 阴性预测值引用偏倚 citation bias 引用偏倚尤登指数 Youden’s index 尤登指数语言偏倚 language bias 语言偏倚预后 prognosis 预后预后因素 prognostic factor 预后因素预后指数 prognostic index 预后指数原始研究证据 primary research evidence 原始研究证据原始研究证据来源 primary resources 原始研究证据来源Z 沾染 contamination 沾染真实性（效度） validity 真实性（效度）诊断参照标准 reference standard of diagnosis 诊断参照标准诊断阈值 testing threshold 诊断阈值诊断﹣治疗阈值 test-treatment threshold 诊断﹣治疗阈值质量调整寿命年 quality adjusted life year，QALY 质量调整寿命年治疗阈值 Treatment threshold 治疗阈值准确度 accuracy 准确度自我评价 self-evaluation 自我评价最佳证据 best evidence最佳证据。

American Thyroid Association Guide to InvestigatingThyroid Hormone Economy and Actionin Rodent and Cell ModelsReport of the American Thyroid Association Task Forceon Approaches and Strategies to Investigate Thyroid Hormone Economy and ActionAntonio C.Bianco,1,*Grant Anderson,2Douglas Forrest,3Valerie Anne Galton,4Bala ´zs Gereben,5Brian W.Kim,1Peter A.Kopp,6Xiao Hui Liao,7Maria Jesus Obregon,8Robin P.Peeters,9Samuel Refetoff,7David S.Sharlin,10Warner S.Simonides,11Roy E.Weiss,7and Graham R.Williams 12Background:An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment approaches for patients with thyroid disease.Summary:Important clinical practices in use today for the treatment of patients with hypothyroidism,hyper-thyroidism,or thyroid cancer are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology.In this document,a panel of experts commissioned by the American Thyroid Association makes a series of recommendations related to the study of thyroid hormone economy and action.These recommendations are intended to promote standardization of study design,which should in turn increase the comparability and reproducibility of experimental findings.Conclusions:It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes.INTRODUCTIONOver the past 150years,investigators utilizing animal and cell culture–based experimental models have achieved landmark discoveries that have shaped our under-standing of thyroid physiology and disease.From the iden-tification of the long-acting thyroid stimulator to the discovery of antithyroid drugs,basic research studies have provided the fundamentals upon which our clinical diag-nostic and therapeutic tools are based.Tens of thousands of publications indexed on PubMed ()fea-ture cells or small animals made hypothyroid or thyrotoxic.The great similarities in multiple aspects of thyroid physi-ology between humans and small rodents have facilitated the rapid translation of experimental findings to the clinical realm.At the same time,fundamental interspecies differences do exist and must be carefully accounted for if the experi-mental findings are to have clinical relevance.1Division of Endocrinology,Diabetes and Metabolism,University of Miami Miller School of Medicine,Miami,Florida.2Department of Pharmacy Practice and Pharmaceutical Sciences,College of Pharmacy,University of Minnesota Duluth,Duluth,Minnesota.3Laboratory of Endocrinology and Receptor Biology,National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,Maryland.4Department of Physiology and Neurobiology,Dartmouth Medical School,Lebanon,New Hampshire.5Department of Endocrine Neurobiology,Institute of Experimental Medicine,Hungarian Academy of Sciences,Budapest,Hungary.6Division of Endocrinology,Metabolism,and Molecular Medicine,and Center for Genetic Medicine,Feinberg School of Medicine,Northwestern University,Chicago,Illinois.7Section of Adult and Pediatric Endocrinology,Diabetes,and Metabolism,The University of Chicago,Chicago,Illinois.8Institute of Biomedical Investigation (IIB),Spanish National Research Council (CSIC)and Autonomous University of Madrid,Madrid,Spain.9Division of Endocrinology,Department of Internal Medicine,Erasmus Medical Center,Rotterdam,The Netherlands.10Department of Biological Sciences,Minnesota State University,Mankato,Minnesota.11Laboratory for Physiology,Institute for Cardiovascular Research,VU University Medical Center,Amsterdam,The Netherlands.12Department of Medicine,Imperial College London,Hammersmith Campus,London,United Kingdom.*Chair;all other authors are listed in alphabetical order.THYROIDVolume 24,Number 1,2014ªAmerican Thyroid Association DOI:10.1089/thy.2013.010988While certain experimental techniques have been widely accepted and adapted following their use in papers gener-ated by influential labs,lack of standardization has un-doubtedly promoted heterogeneity of results.Because certain experimental variables may have unknown biologi-cal threshold levels,lack of standardization may lead to have highly discordant results in different studies examining the same issue.To address this lack of standardization,the American Thyroid Association(ATA)convened a panel of specialists in thefield of basic thyroid research to define consensus strate-gies and approaches for thyroid studies in rodents and in cell models.This task force was charged with reviewing the lit-eraturefirst to determine which experimental practices could benefit from standardization and second to identify critical experimental variables that demand consideration when thyroid studies are being designed.The conclusions of the task force are presented in this document as‘‘American Thyroid Association Guide to Investigating Thyroid Hor-mone Economy and Action in Rodent and Cell Models.’’The 70recommendations and their accompanying commentaries examine topics ranging from‘‘making cells hypothyroid’’to ‘‘how to study the thyrotoxic bone.’’While far from exhaus-tive,these recommendations touch on certain fundamental aspects of thyroid research relevant for all investigators in thefield.Each recommendation in this guide promotes a particular experimental approach based on criteria including the prevalence of the approach,with widely used techniques being given precedence,and in particular whether the ap-proach has been shown to lead to reproducible results in studies by independent investigators.Because head-to-head scientific comparisons of experimental methods in thisfield are virtually nonexistent,these recommendations cannot be graded on the basis of strength of evidence in the fashion of clinical guidelines;indeed,all would be graded as‘‘expert opinion.’’At the same time,unlike clinical guidelines,the main goal of these recommendations and their accompany-ing commentaries is not to identify the single best practice per se,but instead to encourage investigators to choose standard approaches;for example,avoiding random treat-ment doses or methods of thyroid hormone administration, which would only serve to limit comparison with previous studies.The practical nature of recommendations should become readily apparent to the reader.This document is intended to serve as a reference for investigators,assisting them in making design choices that avoid well-known pitfalls while increasing standardization in thefield.As part of this practical approach,reference credit is often given to manuscripts in which the technical details are most clearly or comprehensively explained,rather than thefirst publi-cation to use a technique.In addition,emphasis was placed on contemporary approaches,rather than historical strategies,such that the document illustrates what is cur-rently available for the contemporary study of thyroid hormone homeostasis,metabolism,and action.It is the position of the ATA that animal studies should be per-formed in accordance with all applicable ethical standards and research protocols approved by local institutional animal committees.METHODS OF DEVELOPMENTOF RECOMMENDATIONSAdministrationThe ATA Executive Council selected a chairperson to lead the task force,and this individual(A.C.B.)identified the other14 members of the panel in consultation with the ATA board of directors.Membership on the panel was based on expertise and previous contributions to the thyroidfield.Panel members de-clared whether they had any potential conflict of interest during the course of deliberations.Funding for the guide was derived from the ATA and thus the task force functioned without commercial support.To develop a useful document,the task forcefirst devel-oped a list of the topics that would be most helpful and the most important questions that scientists working in the thy-roidfield might pose when planning an experiment or inter-preting experimental data.Each of the10topics was distributed to a primary writer who used his or her knowl-edge of the subject as well as a systematic PubMed and Google Scholar search for primary references,reviews,and other materials publicly available before December2012,to develop a set of recommendations.All drafts were reviewed and edited by the chair for consistency and sent back to the primary writers for review;in some cases multiple iterations took place until the recommendation wasfinalized.A pre-liminary draft of each recommendation was then reviewed by secondary and tertiary reviewers within the group who then prepared additional critiques.These were addressed by the primary writer and sent back to the chair.All drafts were merged and posted at a protected web address available only to the task force members and ATA office.This document remained available for periodic review by the task force at large,with critiques and suggestions sent back to the chair that updated the document.In a few cases the chair asked for outside experts to critically review specific recommendations given their expertise in a focused area.Their comments and suggestions were then worked into the master document,and the contributions are acknowledged at the end of this article. The panel agreed that recommendations would be based on consensus of the panel.Task force deliberations took place largely through electronic communication.There were also a few meetings of the authors and telephone conference calls. Presentation,Approval,and Endorsementof RecommendationsThe structure of our recommendations is presented in Table 1.Specific recommendations are presented within the main body of the text and in many cases broken down in subitems identified by letters.The page numbers and the location key can be used to quickly navigate to specific topics and recommendations.Prior to the initial submission of these guidelines,they were approved by the board and executive committee of the ATA and afterwards submitted to the membership of the ATA in early2013for comments and suggestions.This feedback was considered in the further preparation of the document that was submitted for publication.Subsequent to the document being accepted for publication in Thyroid,it was approved by the board and executive committee of the ATA.INVESTIGATING THYROID HORMONE ECONOMY AND ACTION89Table anization of the Task Force’s RecommendationsLocation key Sections and subsectionsPage Location key Sections and subsectionsPage T 3,3,3¢,5-triiodothyronine;TR,thyroid hormone receptor;PCR,polymerase chain reaction.[A]Assessing the Thyroid Gland 91[A.1]Structure–function relationships 91Recommendation 191[A.2]Thyroid iodide kinetics 93Recommendation 294Recommendation 395[A.3]Thyroid imaging95Recommendation 495[B]Assessing Circulating and Tissue Thyroid Hormone Levels 97[B.1]Serum97Recommendation 598Recommendation 699Recommendation 7100[B.2]Tissue100Recommendation 8100[B.3]Sources of tissue T 3and TR saturation 100Recommendation 9101[C]Assessing Thyroid Hormone Transport Into Cells101[C.1]Thyroid hormone transport in vitro102Recommendation 10102Recommendation 11103[C.2]Thyroid hormone transport in vivo 103Recommendation 12103[D]Assessing Thyroid Hormone Deiodination 104[D.1]Identification,expression,and quantification of deiodinases 104Recommendation 13104Recommendation 14105[D.2]Deiodination in intact cells 106Recommendation 15106[D.3]Deiodination in perfused organs 106Recommendation 16106[D.4]Deiodination in whole animals 107Recommendation 17107[D.5]Non-deiodination pathways of thyroid hormone metabolism 108Recommendation 18109[E]Inducing Hypothyroidism and Thyroid Hormone Replacement 109[E.1]Hypothyroidism in animals 109Recommendation 19109Recommendation 20110Recommendation 21111Recommendation 22111Recommendation 23112[E.2]Thyroid hormone replacement in animals113Recommendation 24113[E.3]Hypothyroidism in cultured cells 114Recommendation 25114[F]Increasing Thyroid Hormone Signaling114[F.1]Thyrotoxicosis in animals 114Recommendation 26115Recommendation 27115[F.2]Thyrotoxicosis in cultured cells 115Recommendation 28115[F.3]Use of thyroid hormone analogues 116Recommendation 29116[G]Iodine Deficiency and Maternal–Fetal Transfer of Thyroid Hormone 117[G.1]Iodine deficiency in rodents 117Recommendation 30117Recommendation 31118Recommendation 32118[G.2]Placental transfer of thyroid hormone 118Recommendation 33118[H]Models of Nonthyroidal Illness118Recommendation 34119Recommendation 35119[I]Assessing Thyroid Hormone Signaling at Tissue and Cellular Levels 119[I.1]Gene expression as a marker of thyroid hormone status 120Recommendation 36120[I.2]PCR analysis of mRNA expression levels 120Recommendation 37120[I.3]Genome-wide analysis of thyroid hormone-responsive mRNA 122Recommendation 38122[I.4]Mechanisms of gene regulation by thyroid hormone122Recommendation 39122Recommendation 40123[I.5]Mouse models for indicating thyroid hormone and TR signaling in tissues 123Recommendation 41124[J]Assessing Thyroid Hormone Signaling by Way of Systemic Biological Parameters 124[J.1]Central nervous system 125Recommendation 42126Recommendation 43126Recommendation 44127Recommendation 45127Recommendation 46127Recommendation 47128Recommendation 48128[J.2]Heart and cardiovascular system 129Recommendation 49129Recommendation 50129Recommendation 51130Recommendation 52130Recommendation 53131Recommendation 54132[J.3]Intermediary metabolism and energy homeostasis 132Recommendation 55132Recommendation 56135Recommendation 57135Recommendation 58136Recommendation 59137[J.4]Skeletal muscle137Recommendation 60138Recommendation 61138Recommendation 62138Recommendation 63139Recommendation 64139Recommendation 65139[J.5]Skeleton140Recommendation 66140Recommendation 67140Recommendation 68140Recommendation 69140Recommendation 7014290Thefinal document was officially endorsed by the American Academy of Otolaryngology–Head and Neck Surgery(AAO-HNS),American Association of Endocrine Surgeons(AAES), American College of Nuclear Medicine(ACNM),Asia and Oceania Thyroid Association(AOTA),British Nuclear Medi-cine Society(BNMS),British Thyroid Association(BTA), European Thyroid Association(ETA),International Associa-tion of Endocrine Surgeons(IAES),Italian Endocrine Society (SIE),Japan Thyroid Association(JTA),Korean Society of Head and Neck Surgery(KSHNS),Latin American Thyroid Society(LATS),Korean Society of Nuclear Medicine(KSNM) and The Endocrine Society(TES).RESULTS[A]Assessing the Thyroid GlandOverview.Studies of function–structure relationship of the thyroid gland,as well as studies of thyroid iodide kinetics and imaging are traditionally employed to assess the thyroid gland.Structural characterization is important to assess functional changes such as hypo-and hyperthyroidism and for evaluating transformation of thyroid cells into a malignant phenotype(1–3).At the same time,the study of thyroidal iodide economy and thyroid imaging are relevant not only to studies of thyroid hormone synthesis but also to under-standing the effects of environmental toxins such as perchlo-rate or thiocyanate on thyroid economy(4–7).[A.1]Structure–function relationshipsBackground.While the human thyroid consists of a left and a right lobe that are connected by an isthmus,rodents have two independent thyroid lobes.The thyroid gland is divided by connective tissue septa into lobules,each one of these containing from20to40follicles,the basic functional unit of the thyroid gland.The follicle is a round or elongated hollow structure lined by a single layer of polarized cuboidal orflattened follicular cells that isfilled with thyroglobulin-containing colloid.It is surrounded by a basal membrane and a rich capillary network with high bloodflow(8).The follicles normally vary considerable in size,and the follicular cell morphology is usually monotonous.The height of the cells varies according to the functional status of the gland.&RECOMMENDATION1aMorphometry of thyroid follicles can be used as an index of thyroidal activity.Commentary.The entire gland should always be dis-sected while attached to the trachea and immediatelyfixed with10%neutral buffered formalin for histological and im-munohistochemical analysis.Hematoxylin and eosin(H&E) staining is widely used to assess the thyrocytes,whereas periodic-acid Schiff staining stains thyroglobulin avidly and is well suited to highlight follicular protein content and follic-ular structure(Fig.1)(8).Structural modifications reflect changes in secretory activity resulting from iodine deficiency (9),chronic cold exposure(10),or treatment with antithyroid drugs(11).Some follicular cell parameters such as height can be measured under light microscopy using an ocular mi-crometer grid(e.g.,in a1-month-old rat,the epithelial cell height is about10l m)(12).Aflat epithelium is hypoactive,while a heightened epithelium is observed in glands in which the thyrotropin(TSH)pathway is stimulated(10).The use of computerized semiautomatic image analysis is more objective and used widely(13).Such morphometric analysis should be focused on one of the central sections of the thyroid(13)that is representative of the whole lobe(14).The data obtained are reduced by predefined mathematical models that assume thyroid follicles have a spherical shape and follicular cells are octagons with a square base.This data reduction yields the following parameters:mean follicle circumference;surface area and volume;total volume of epithelium and colloid; number of epithelial cell nuclei visible in each follicle;and the height,surface area,and volume of thyroid epithelial cell, which can be used to estimate the functional state of the thyroid gland.Thus,the activation index,expressed by the epithelial volume/colloid volume ratio,increases as the thy-roid becomes more active,reflecting an increase in the epi-thelial volume and a decrease in the colloid volume(13). Measurement of total cell volume in cultures of primary thyrocytes or cell lines cultured in vitro can be performed using confocal laser-scanning microscopy after cells are loa-ded with octadecylrhodamine B(15,16).FIG.1.Microscopic structure of the mouse thyroid.(A) Hematoxylin and eosin(H&E)staining.(B)Periodic acid Schiff(PAS)staining.Mice were euthanized,and the thy-roids dissected,fixed in buffered formalin,and embedded in paraffin.Thyroid sections(5l m)were mounted on glass slides,de-paraffinated,and hydrated.For histological anal-ysis,sections were stained with H&E,following a standard protocol.Glycoproteins were detected using PAS staining. Sections were stained with0.5%periodic acid for30minutes and with Schiff’s reagent for20minutes and then rinsed in running tap water for5minutes.Nuclei were counterstained with hematoxylin for3minutes.Sections were rinsed in running tap water,dehydrated,cleared,and mounted.Re-produced with permission from Senou et al.(20).INVESTIGATING THYROID HORMONE ECONOMY AND ACTION91&RECOMMENDATION 1bAutoradiography can be used to quantify the overall ac-tivity of thyroid follicles and to determine the location of iodide within follicles.Commentary.Thyroid follicular cells concentrate iodide according to their activity.Although the activity of the thou-sands of follicular cells should be similar within a given thy-roid gland,there is a great deal of variation among cells within the same follicle and between follicles.Thus autoradiography provides unique insights into the activity of individual thy-roid follicular cells.125I is injected intravenously,typically 48to 72hours prior to killing the animal.Thyroid glands are dissected and processed for autoradiography using standard techniques (17,18).Orga-nification of iodide can be blocked by treatment of the animals with methimazole (MMI).Autoradiography experiments with human,rodent,and feline goiter tissue have also been per-formed after xenotransplantation of thyroid tissue into nude mice.Subcutaneously implanted fragments are maintained in recipient mice for several weeks before further analysis (19).&RECOMMENDATION 1cThe ultrastructural distribution of iodide within thyroid follicles can be defined with secondary ion mass spec-trometry (SIMS).Commentary.SIMS is a technique used to analyze the composition of thin films by sputtering the surface of the specimen with a focused primary ion beam and collecting and analyzing ejected secondary ions (Fig.2).The mass/charge ratios of these secondary ions are measured with a mass spectrometer to determine the elemental,isotopic,or molec-ular composition of the surface to a depth of 1–2nm.SIMS is the most sensitive surface analysis technique,with elementaldetection limits ranging from parts per million to parts per billion.It is uniquely suited for the study of trace ions distri-bution at the ultrastructural level (20).Ionic images show that the early distribution of iodine is heterogeneous from one follicle to another,from one thyr-ocyte to another inside the same follicle,and that this dis-tribution varies as a function of time (21).In normal thyroids the natural 127I isotope is found predominantly in the fol-licular lumina.The identification of lumina devoid of 127I and/or the demonstration of significant amounts of 127I in the cytoplasm of the epithelial cells or on the apical mem-brane indicates impairment of the iodination pathway.To define the ultrastructural distribution of iodide using SIMS,thyroid lobes are processed in a similar way as for electron microscopy,including fixation with glutaraldehyde and preparation of semithin sections (20).&RECOMMENDATION 1dConfocal microscopy in conjunction with immunohisto-chemistry (IHC)can be used for two-or three-dimensional (2D or 3D)image reconstruction to study protein expres-sion in thyroid follicles,the surrounding capillary network,and the stroma.Commentary.Antibodies are available against most key proteins in thyrocyte biology (22,23).Thus,standard IHC techniques are commonly used in thyroid studies (Figs.3and 4)(24,25).Visualization can be performed with conventional light microscopy,immunofluorescence microscopy,or con-focal microscopy for higher resolution and 2D or 3D image reconstruction (26).Cell surface proteins and processes are best investigated using scanning electron microscopy (10).Endogenous peroxidase activity is very high in thyroid cells and is detected by reacting fixed tissue sections with 3,3¢-diaminobenzidine substrate;pretreatment withhydrogenFIG.2.Mouse thyroid transmission electron microscopy.Thyroid lobes were fixed in 2.5%glutaraldehyde in 0.1M cacodylate buffer for 1.5hours,post-fixed in 1%osmium tetroxide for 1hour,and embedded in LX112resin (Ladd Research Industries,Burlington,VT).(A)Thin sections (0.5l m)were stained with toluidine blue and analyzed for morphology by light microscopy.(B)Ultrathin sections were prepared and stained with uranyl acetate and lead citrate and examined with an electron microscope Zeiss EM169(Carl Zeiss,Oberkochen,Germany).(C)Ultrastructural distribution of 127I by secondary ion mass spectrometry (SIMS)imaging.Semi-thin sections were prepared,and the ultrastructural distribution of the iodide natural isotope (127I)was obtained through imaging by SIMS,using the NanoSIMS 50system.Maps were acquired under standard analytic conditions:a Cs +primary beam with impact energy of 16keV and a probe with current intensity of 1pA.The analyzed surface was 30·30l m.Under these conditions,a lateral resolution of 100nm is expected.All images were acquired in 256·256pixels with a counting time of 20milliseconds per pixel.White areas correspond to iodine detection.127I is homogeneously distributed in the follicular lumina and in a few intracytoplasmic vesicles.Reproduced with permission from Senou et al.(20).92BIANCO ET AL.peroxide prior to incubation with primary antibody eliminates endogenous peroxidase activity that will interfere in IHC studies.The use offluorescent-tagged proteins should be avoi-ded if autofluorescence is a problem(as assessed by viewing tissue sections with afluorescence microscope before any anti-body incubation).Fine subcellular distribution studies can be done with IHC and confocal microscopy;immunogold staining electron microscopy allows detection of antigens at very high resolution in studies of subcellular distribution(Fig.5) (20,27).[A.2]Thyroid iodide kineticsBackground.The synthesis of thyroid hormone,its tetra-iodinated form thyroxine(T4),and3,3¢,5-triiodothyronine(T3) requires a normally developed thyroid gland,an adequate io-dide intake,and a series of regulated biochemical steps in thyroid follicular cells,which form the spherical thyroid folli-cles,the functional unit of the thyroid gland(28).In thyroid epithelial cells,the sodium iodide symporter(NIS)mediates the iodide uptake into thyroid follicular cells(29),and its ex-pression is polarized(i.e.,it is expressed only in the basolateral membrane).At the basolateral membrane of thyrocytes,Na+/ K+-ATPase generates a sodium gradient that permits NIS to mediate perchlorate inhibitable,Na+-dependent iodide uptake (30).Iodide then translocates to the apical membrane and reaches the follicular lumen through the apical membrane. While it has been assumed that iodide moves across the apical membrane primarily because of the electrochemical gradient, studies in frozen section demonstrated that it isfirst accumu-lated in the cytoplasm and only later in the lumen,and apical iodide efflux is rapidly accelerated in polarized cells after ex-posure to TSH(31).Electrophysiological studies using inverted plasma membrane vesicles suggested the existence of two apical iodide channels,but their molecular identity has not been determined(32).The multifunctional anion exchanger pendrin(SLC26A4/PDS),which has affinity for anions such as iodide,chloride,and bicarbonate is thought to represent one of these entities(33,34).Both NIS and SLC26A4expression and activity are increased by TSH(30,33).While the term iodide uptake can be used broadly for in vitro and in vivo approaches, data interpretation should take into account the critical differ-ences between the two settings,with the former reflecting cel-lular iodide uptake and the latter mainly the concentration of organified iodine in thecolloid.FIG.4.Detection of dual oxidase(DUOX)and thyroperoxidase inthe mouse thyroid by immunohis-tochemistry.(A)DUOX was de-tected on frozen sections with rabbitpolyclonal antibody diluted1/3000and incubated overnight.Positivityis observed at the apical pole(arrows,inset).(B)thyroperoxidasewas detected on paraffin sectionswith rabbit antibody Lo a d TPO821,4l g/mL and incubated for3hours.Reproduced with permis-sion from Senou et al.(20).FIG.3.Detection of thyroglobulin and iodinated thyro-globulin in the mouse thyroid by immunohistochemistry.(A)Thyroglobulin was detected on paraffin sections using anti-thyroglobulin rabbit polyclonal antibody(Dako)diluted1/1500and incubated overnight.(B)Iodinated thyroglobulinwas detected using mouse monoclonal antibody(B1)diluted1/3000and incubated overnight.Negative controls includedthe replacement of primary antibody by the preimmuneserum or absence of the primary antibody.Reproduced withpermission from Senou et al.(20).INVESTIGATING THYROID HORMONE ECONOMY AND ACTION93。

Intensive Care Med (2018) 44:2276–2278 https:///10.1007/s00134-018-5306-6Innovation and safety in critical care:should we collaborate with the industry? Pro Anthony C. Gordon1,2* and James A. Russell3,4© 2018 Springer-Verlag GmbH Germany, part of Springer Nature and ESICMAs clinicians we all want to improve care for our patients. We can do that in two ways. We can do what we currently do better, or we can do new things (better). The devel-opment of large clinical academic trials groups and net-works has enabled clinicians to understand what particu-lar clinical care leads to better patient-centred outcomes. Ironically, we have learnt that many of our “usual” inter-ventions either provided no benefit or were even harmful. Thus, clinicians, can improve the safety and effectiveness of critical care practice. But when it comes to innova-tion—new therapeutics and novel diagnostics—then it is hard to imagine that we could achieve this without input from or partnership with industry. Furthermore, a brief walk around an ICU illustrates cogently the vast num-ber of devices used and drugs being infused, all of which originated in industry, some with much and some with little clinician scientist input. We argue herein that such collaboration is not only acceptable, it is also necessary and can be done ethically, using established guidelines and conflict of interest disclosure.Sceptics point out that there have been few new thera-peutics in routine critical care despite industry’s repeated attempts in recent decades. But that does not mean that we should abandon working with industry. One indeed might argue that more thought-leader and bedside cli-nician input is needed in the discovery (selecting tar-gets) and validation (better trial design using better patient-centred outcomes) stages. In other medical spe-cialties, innovations from industry have revolutionised patient management and improved outcomes. HIV care and outcomes were completely changed within a gen-eration because of multi-drug antiretroviral therapy that was developed in conjunction with industry [1]. Immune checkpoint inhibitors and other immunotherapies are now transforming oncology. If we want similar success in critical care then we argue that it is vital that we col-laborate with industry to strengthen the underpinning science and later clinical development.It is frequently reported that industry-sponsored research is more likely to publish positive findings from clinical trials than academically sponsored trials [2]. The reasons for this are likely multi-factorial. Certainly, the plethora of industry-sponsored “me-too” drug and device trials where new interventions are shown to be non-inferior to current drugs and devices minimally advances care. The requirement for prospective trial registration should mitigate delayed or selective publication of unfa-vourable results. We contend that academic collaborators in industry-led research should push industry to con-tinue to improve in this area.We and others suggest that the chances of more posi-tive trials could increase by using better methodology. The competitive market place requires stringent criteria for industry to select only the most promising early stage agents to progress to the really expensive stage—clinical development. The subsequent trials methodology must be strong. Some studies report industry collaboration trials were more likely to use high-quality methods than trials without industry funding [3]. Other reports found limited but important differences; industry studies were more likely to be at low risk of bias because of blinding but more likely to yield conclusions that did not align with the results compared with non-industry studies [2].*Correspondence:**************************.uk1 Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, UKFull author information is available at the end of the articleFor contrasting viewpoints, please go to https:///10.1007/s0013 4-018-5295-5The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.2277Of course, there need to be appropriate checks and balance. There are always concerns about the risk of bias when money is involved but there are plenty of other sources of bias that may be as, if not more, important [4]. There are well-established and evolving guidelines for ethical conduct of academics with industry regard-ing disclosure of conflicts of interest such as the Sunshine Act in the USA requiring industry to disclose annually its payments to physicians [5]. Any agreements between academia and industry, including payments both directly to the individual and to their institution (which may play a valuable role in supporting an academic labora-tory), should be disclosed so that reviewers and readers can evaluate possible bias. Although payments direct to physicians have a clear potential to be a conflict of inter-est, payments to institutions also have this potential and so should be declared too. Robust contracts ensure that the highest standards of research are maintained, includ-ing publishing protocols and analytical plans prospec-tively and agreeing that all results will be made public in a timely fashion, regardless of the study outcome. Rules over intellectual property must be agreed in advance. Fortunately, there are well-established principles [e.g., Lambert agreement used by the UK Medical Research Council (MRC)] that standardise template contracts to unify university-industry research collaborations. Although harder to quantify, academic bias is now rec-ognised as another potential source of bias to be consid-ered. Requirements to publish and bring in grant income to academic institutions are still key measures to achieve promotion and tenure. It is still easier to publish positive results in high-impact journals and secure the next big grant based on positive results of previous work. It can be argued that a lifelong tenured academic position is probably worth more in financial terms than a short-term industry collaboration.The benefits of industry-academic collaborations are recognised by major medical grant-giving bodies that have joint industry-academic grant schemes (e.g., UK NIHR Invention for Innovation fund [6], Wellcome Trust’s Health Innovation Challenge Fund [7], EU Inno-vative Medicines Initiative [8]). Relevant to critical care is the recent Experimental Medicine Initiative to Explore New Therapies (EMINENT) network supported by the UK MRC and with matched support from GSK that pro-vides unique access to a portfolio of experimental drug compounds [9]. Academic researchers from five universi-ties will work with industry partners to better understand the mechanisms of inflammatory and fibrotic lung dis-ease to then develop new treatments.As critical care understands how genomics influ-ences patient outcomes and response to treatment [10], collaborations such as the Structural Genomics Con-sortium will be key to drive innovative research in this area [11]. This not-for-profit organisation, with multiple academic and industry partners, provides an open col-laborative network so that its research is available to the scientific community with no strings attached.The benefits of such public-private collaborations are recognised by governments throughout the world. The recent UK Life Sciences: industrial strategy points out that innovation is key to improving outcomes for patients but also lays out the case for public investment in bio-medical and health research to improve outcomes and to deliver strong economic growth [12]. We as clinical academics must drive this agenda for the health of our patients as well as the wealth of our nations.If clinician-scientists and clinicians choose not to col-laborate and consult with industry, then industry will push ahead without us. Industry employs clinicians, but many will have given up clinical work some years ago and so can be out of touch with current clinical prac-tice. Accordingly, we need the best practising clinicians to help guide research development. Although industry’s fundamental objective is to generate profit for its share-holders, if it develops effective treatments then two com-plementary objectives can be achieved—better outcomes for patients and increased revenue for industry. Again, the HIV story illustrates this paradigm.Clinical scientists will continue to innovate but if we want to translate this into improved patient care we need industry collaboration. A good example comes from this journal recently, where academic investigators dem-onstrated that cell surface markers predict risk of sub-sequent infection (INFECT study [13]). Collaboration with industry was an essential ingredient to conduct this multi-centre study, to provide standardised assays across all sites over time and to allow appropriate and meaning-ful analysis, interpretation and publication.In conclusion, there are undoubtedly exciting innova-tions around the corner for critical care, including rapid pathogen detection, -omic technologies to stratify and personalise patient care [14, 15], artificial intelligence to aid diagnoses and treatment decisions [16], new immu-nostimulation [17] and stem cell therapies [18]. To think that we as clinical academics can develop these on a large scale, on our own, is naïve and we should there-fore actively collaborate with our industry colleagues to robustly test them and make them a reality for our patients.Author details1 Section of Anaesthetics, Pain Medicine and Intensive Care, Departmentof Surgery and Cancer, Imperial College London, London, UK. 2 Intensive Care2278Unit, Imperial College Healthcare NHS Trust, St Mary’s Hospital, London, UK.3 Centre for Heart Lung Innovation (HLI), Vancouver, Canada.4 Division of Criti-cal Care Medicine, St. Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.AcknowledgementsACG is funded by a National Institute of Health Research (NIHR) Research Pro-fessorship award (RP-2015-06-018) and supported the NIHR Comprehensive Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.Compliance with ethical standardsConflicts of interestACG: reports that he has received speaker fees from Orion Corporation Orion Pharma and Amomed Pharma. He has consulted for Ferring Pharmaceuti-cals, Tenax Therapeutics, Baxter Healthcare, Bristol-Myers Squibb and GSK and received grant support from Orion Corporation Orion Pharma, Tenax Therapeutics and HCA International with funds paid to his institution. JAR (last 36 months): Dr. Russell reports patents owned by the University of British Columbia (UBC) related to PCSK9 inhibitor(s) and sepsis and related to the use of vasopressin in septic shock. Dr. Russell is an inventor on these patents. Dr. Russell is a founder, Director and shareholder in Cyon Therapeutics Inc. [developing a sepsis therapy (PCSK9 inhibitor)]. Dr. Russell has share options in Leading Biosciences Inc. Dr. Russell is a shareholder in Molecular You Corp. Dr. Russell reports receiving consulting fees in the last 3 years from: (1) Asahi Kesai Pharmaceuticals of America (AKPA) (developing recombinant thrombomodu-lin in sepsis); (2) La Jolla Pharmaceuticals (developing angiotensin II; Dr. Russell chaired the DSMB of a trial of angiotensin II from 2015 to 2017)—no longer actively consulting; (3) Ferring Pharmaceuticals (manufactures vasopressin and was developing selepressin)—no longer actively consulting; (4) Cubist Pharmaceuticals (now owned by Merck; formerly was Trius Pharmaceuticals; developing antibiotics)—no longer actively consulting; (5) Leading Bio-sciences (was developing a sepsis therapeutic that is no longer in develop-ment)—no longer actively consulting; (6) Grifols (sells albumin)—no longer actively consulting; (7) CytoVale Inc. (developing a sepsis diagnostic)—no longer actively consulting. Dr. Russell reports having received an investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic shock?”) that is provided to and administered by UBC.Received: 21 June 2018 Accepted: 4 July 2018Published online: 8 November 2018References1. Lima VD, Lourenco L, Yip B, Hogg RS, Phillips P, Montaner JS (2015)AIDS incidence and AIDS-related mortality in British Columbia, Canada, between 1981 and 2013: a retrospective study. Lancet HIV 2:e92–e97 2. Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L (2017) Industry sponsor-ship and research outcome. Cochrane Database Syst Rev 2:MR0000333. Linker A, Yang A, Roper N, Whitaker E, Korenstein D (2017) Impact ofindustry collaboration on randomised controlled trials in oncology. Eur J Cancer 72:71–774. Rosenbaum L (2015) Understanding bias–the case for careful study. NEngl J Med 372:1959–19635. Chimonas S, DeVito NJ, Rothman DJ (2017) Bringing transparency tomedicine: exploring physicians’views and experiences of the SunshineAct. Am J Bioeth 17:4–186. https:///fundi n g-and-suppo r t/fundi n g-for-resea r ch-studies/fundi n g-progr a mmes/inven t ion-for-innov a tion/. Accessed 18 July20187. https://wellc o /what-we-do/direc t orie s/healt h-innov a tion-challenge-fund-proje c ts-funde d. Accessed 18 July 20188. https://www.imi.europ a.eu/. Accessed 18 July 20189. https:///news/brows e/mrc-gsk-and-five-leadi n g-uk-unive r sities-colla b orat e-to-crack-diffi c ult-disea s e-areas/. Accessed 18 July 201810. Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R,Chiche JD, Parks T, Chapman SJ, Davenport EE, Elliott KS, Bion J, Lichtner P, Meitinger T, Wienker TF, Caulfield MJ, Mein C, Bloos F, Bobek I, Cotogni P, Sramek V, Sarapuu S, Kobilay M, Ranieri VM, Rello J, Sirgo G, Weiss YG,Russwurm S, Schneider EM, Reinhart K, Holloway PA, Knight JC, Garrard CS, Russell JA, Walley KR, Stuber F, Hill AV, Hinds CJ, EEG Investigators(2015) Genome-wide association study of survival from sepsis due topneumonia: an observational cohort study. Lancet Respir Med 3:53–6011. https://www.thesg /. Accessed 18 July 201812. Bell J (2017) Life sciences: industrial strategy13. Conway-Morris A, Wilson J, Shankar-Hari M (2018) Immune activation insepsis. Crit Care Clin 34:29–4214. Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, MillsTC, Rautanen A, Gordon AC, Garrard C, Hill AV, Hinds CJ, Knight JC (2016) Genomic landscape of the individual host response and outcomes insepsis: a prospective cohort study. Lancet Respir Med 4:259–27115. Russell JA, Spronk P, Walley KR (2018) Using multiple ‘omics strategies fornovel therapies in sepsis. Intensive Care Med 44:509–51116. Komorowski M, Celi LA, Badawi O, Gordon AC, Faisal AA (2018) Theintensive care AI clinician learns optimal treatment strategies for sepsis.Nat Med. https:///10.1038/s41591-018-0213-517. Francois B, Jeannet R, Daix T, Walton AH, Shotwell MS, Unsinger J,Monneret G, Rimmele T, Blood T, Morre M, Gregoire A, Mayo GA, BloodJ, Durum SK, Sherwood ER, Hotchkiss RS (2018) Interleukin-7 restores lym-phocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight 3:e9896018. McIntyre LA, Stewart DJ, Mei SHJ, Courtman D, Watpool I, Granton J, Mar-shall J, Dos Santos C, Walley KR, Winston BW, Schlosser K, Fergusson DA, Canadian Critical Care Trials G, Canadian Critical Care Translational BiologyG (2018) Cellular immunotherapy for septic shock. A phase I clinical trial.Am J Respir Crit Care Med 197:337–347。

EUROPEAN COMMISSIONDIRECTORATE GENERAL for HEALTH and CONSUMERSConsumer AffairsHealth technology and CosmeticsNoteThe present Guidelines are part of a set of Guidelines relating to questions of application of EC-Directives on medical Devices. They are legally not binding. The Guidelines have been carefully drafted through a process of intensive consultation of the various interest parties (competent authorities, Commission services, industries, other interested parties) during which intermediate drafts where circulated and comments were taken up in the document. Therefore, this document reflects positions taken by representatives of interest parties in the medical devices sector.CONTENTS12341. Introduction (3)52. Scope (4)63. References (4)74. Definitions (6)85. Circumstances where a post market clinical follow up study in indicated (8)96. Elements of a post-market clinical follow up study (10)107. The use of study data (12)118 The role of the notified body in post-market clinical follow up (12)121314Preface15This document is intended to be a guide for manufacturers and Notified Bodies on 16how to carry out Post-Market Clinical Follow-up (PMCF) studies in order to fulfil 17Post-Market Surveillance (PMS) obligations according to Section 3.1 of Annex II, 18Section 3 of Annex IV, Section 3 of Annex V, Section 3.1 of Annex VI or Section 4 19of Annex VII of the Medical Devices Directive (93/42/EEC) and Section 3.1 of 20Annex 2, Section 3 of Annex 4, Section 3.1 of Annex 5 of the Active Implantable 21Medical Devices Directive (90/385/EEC). These Sections refer to requirements of 22Annex X of Directive 93/42/EEC and Annex 7 of Directive 90/385/EEC, respectively.2324Attention is drawn to paragraph 8 of Article 15 of Directive 93/42/EEC which spells 25out the provisions of Article 15 that are not applicable to clinical investigations26conducted using CE-marked devices within their intended use.27Similarly when PMCF studies are conducted using CE marked devices within their28intended use, the provisions of section 2.3.5 of Annex X of Directive 93/42/EEC do 29not apply. However, the provisions of Directive 93/42/EEC concerning information 30and notification of incidents occurring following placing devices on the market are31fully applicable.321. Introduction3334While clinical evidence is an essential element of the premarket conformity 35assessment process to demonstrate conformity to Essential Requirements, it is 36important to recognise that there may be limitations to the clinical data available in 37the pre-market phase. Such limitations may be due to the duration of pre-market 38clinical investigations, the number of subjects and investigators involved in an 39investigation, the relative heterogeneity of subjects and investigators and/or the 40controlled setting of a clinical investigation versus the full range of clinical conditions 41encountered in general medical practice.4243A precondition for placing a product on the market is that conformity to the relevant44Essential Requirements, including a favourable benefit/risk ratio, has been 45demonstrated. The extent of the data that can be gathered in the pre-market phase 46does not necessarily enable the manufacturer to detect rare complications or problems 47that only become apparent after wide-spread or long term use of the device. As part of 48the manufacturer’s quality system, an appropriate post-market surveillance plan is key 49to identifying and investigating residual risks associated with the use of medical 50devices placed on the market. These residual risks should be investigated and assessed 51in the post-market phase through systematic Post-Market Clinical Follow-up (PMCF) 52study(ies).5354Clinical data obtained from post-market surveillance and during PMCF studies by the 55manufacturer are not intended to replace the pre-market data necessary to demonstrate 56conformity with the provisions of the legislation. However, they are critical to update 57the clinical evaluation throughout the life-cycle of the medical device and to ensure 58the long term safety and performance of devices after their placing on the market.5960PMCF studies are one of several options available in post-market surveillance and 61contribute to the risk management process.62636465662. Scope6768The objective of this document is to provide guidance on the appropriate use and 69conduct of PMCF studies to address issues linked to residual risks. The intention is 70not to impose new regulatory requirements.7172PMCF studies are an important element to be considered in PMCF or PMS plans. The 73principles for PMCF studies set out in this guidance are not intended to replace PMCF 74or PMS plans. They are or may be applicable to PMCF studies conducted for other 75purposes.7677This document provides guidance in relation to:78i)the circumstances where a PMCF study is indicated;79ii)the general principles of PMCF studies involving medical devices;80iii) the use of study data (for example to update instructions for use and labelling);81and82iv)the role of a notified body for medical devices in the assessment of PMCF plans 83and of the results obtained from the plans as part of conformity assessment.8485This document does not apply to in vitro diagnostic devices.86873. References8889Council Directive 93/42/EEC of 14 June 1993 concerning medical devices as last 90amended by Directive 2007/47/EC of the European Parliament and of the Council of 915 September 2007.9293Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of 94the Member States relating to active implantable medical devices last amended by95Directive 2007/47/EC of the European Parliament and of the Council of 5 September 962007.979899100Interpretative Documents101102MEDDEV 2.7.1 Clinical Evaluation: A Guide for Manufacturers and Notified103Bodies104105106MEDDEV 2.7.1, Appendix 1Evaluation of Clinical Data – A Guide for Manufacturers and107Notified Bodies –Appendix 1: Clinical Evaluation of Coronary 108Stents109110111GHTF Final Documents:112SG1/N41:2005Essential Principles of Safety & Performance of Medical Devices 113SG1/N44:2008The Role of Standards in the Assessment of Medical Devices114SG1/N065:2010Registration of Manufacturers and Other Parties and Listing of 115Medical Devices116SG2/N47:2005Review of Current Requirements on Post-Market Surveillance117SG5/N1:2007Clinical Evidence – Key Definitions and Concepts118SG5/N2:2007Clinical Evaluation119SG5/N3:2010Clinical Investigations120121122International Standards:123EN ISO 14155:2011Clinical investigation of Medical Devices for human subjects 124Good clinical practice; Second edition 2011-02-01125126EN ISO 14971:2009 Application of risk management to medical devices127128Others:129US Department of Health and Human Service, Agency for Healthcare Research 130and Quality:131R egistries for Evaluating Patient Outcomes: a User’s Guide(Executive 132Summary, April 2007).1331341351361374. Definitions138139140Clinical Data1:141The safety and/or performance information that is generated from the use of a 142device.143Clinical data are sourced from:144-clinical investigation(s) of the device concerned; or145-clinical investigation(s) or other studies reported in the scientific literature 146of a similar device for which equivalence to the device in question can be 147demonstrated; or148-published and/or unpublished reports on other clinical experience of either 149the device in question or a similar device for which equivalence to the 150device in question can be demonstrated.151152Clinical Evaluation2:153The assessment and analysis of clinical data pertaining to a medical device to 154verify the clinical safety and performance of the device when used as intended 155by the manufacturer.156157Clinical Evidence2:158The clinical data and the clinical evaluation report pertaining to a medical 159device.160161Clinical Investigation2:162Any systematic investigation or study in or on one or more human subjects, 163undertaken to assess the safety or performance of a medical device.164165Device Registry3:166An organised system that uses observational study methods to collect defined 167clinical data under normal conditions of use relating to one or more devices to 1681Council Directives 90/385/EEC and 93/42/EEC2 GHTF document SG5/N1R8: 2007: Clinical Evidence – Key Definitions and Concepts3GHTF document SG5/N4:2010: Post Market Clinical Follow-Up Studies, based on the definition inAgency for Healthcare Research and Quality, “Registries for Evaluating Patient Outcomes: A User’sGuide”, as modified.evaluate specified outcomes for a population defined by a particular disease, 169condition, or exposure and that serves predetermined scientific, clinical or 170policy purpose(s).171172Note: The term “device registry” as defined in this guidance should not be 173confused with the concept of device registration and listing. (See GHTF 174SG1N065)175176Post-market clinical follow-up (PMCF) study:177A study carried out following the CE marking of a device and intended to 178answer specific questions relating to clinical safety or performance (i.e. residual 179risks) of a device when used in accordance with its approved labelling.180181PMCF plan:182The documented, proactive, organised methods and procedures set up by the 183manufacturer to collect clinical data based on the use of a CE-marked device 184corresponding to a particular design dossier or on the use of a group of medical 185devices belonging to the same subcategory or generic device group as defined 186in Directive 93/42/EEC. The objective is to confirm clinical performance and 187safety throughout the expected lifetime of the medical device, the acceptability 188of identified risks and to detect emerging risks on the basis of factual evidence. 189190Residual Risk:191Risk remaining after risk control measures has been taken4 .1921934EN ISO 149711945. Circumstances where a PMCF study is indicated195196Following a proper premarket clinical evaluation, the decision to conduct PMCF 197studies must be based on the identification of possible residual risks and/or unclarity 198on long term clinical performance that may impact the benefit/risk ratio.199200PMCF studies may review issues such as long-term performance and/or safety, the 201occurrence of clinical events (e.g. delayed hypersensitivity reactions, thrombosis), 202events specific to defined patient populations, or the performance and/or safety of the 203device in a more representative population of users and patients.204205Circumstances that may justify PMCF studies include, for example:206∙innovation, e.g., where the design of the device, the materials, substances, 207the principles of operation, the technology or the medical indications are 208novel;209∙significant changes to the products or to its intended use for which pre-210market clinical evaluation and re-certification has been completed;211∙high product related risk e.g. based on design, materials, components, 212invasiveness, clinical procedures;213∙high risk anatomical locations;214∙high risk target populations e.g. paediatrics, elderly;215∙severity of disease/treatment challenges;216∙questions of ability to generalise clinical investigation results;217∙unanswered questions of long-term safety and performance;218219∙results from any previous clinical investigation, including adverse events or from post-market surveillance activities;220∙identification of previously unstudied subpopulations which may show 221different benefit/risk-ratio e.g. hip implants in different ethnic 222populations;223∙continued validation in cases of discrepancy between reasonable 224premarket follow-up time scales and the expected life of the product;225∙risks identified from the literature or other data sources for similar 226marketed devices;227∙interaction with other medical products or treatments;228∙verification of safety and performance of device when exposed to a larger 229and more varied population of clinical users;230∙emergence of new information on safety or performance;231∙where CE marking was based on equivalence.232233PMCF studies may not be required when the medium/long-term safety and clinical 234performance are already known from previous use of the device or where other 235appropriate post-market surveillance activities would provide sufficient data to 236address the risks.2372382392402412426. Elements of a PMCF study243244Post-market clinical follow-up studies are performed on a device within its intended 245use/purpose(s) according to the instructions for use. It is important to note that PMCF 246studies must be conducted according to applicable laws and regulations and should 247involve an appropriate methodology and follow appropriate guidance and standards. 248249PMCF studies must be outlined as a well designed clinical investigation plan or study 250plan, and, as appropriate, include:251∙clearly stated research question(s), objective(s) and related endpoints;252∙scientifically sound design with an appropriate rationale and statistical analysis 253plan;254255∙a plan for conduct according to the appropriate standard(s);256∙a plan for an analysis of the data and for drawing appropriate conclusion(s).257Objectives of PMCF studies258The objective(s) of the study should be stated clearly and should address the residual 259risk(s) identified and be formulated to address one or more specific questions relating 260to the clinical safety or clinical performance of the device. A formal hypothesis 261should be clearly expressed.262263Design of PMCF studies264PMCF studies should be designed to address the objective(s) of the study. The design 265may vary based on the objective(s), study hypothesis research question and endpoints 266and should be scientifically sound to allow for valid conclusions to be drawn.267268PMCF studies can follow several methodologies, for example:269∙the extended follow-up of patients enrolled in premarket investigations;270∙ a new clinical investigation;271∙ a review of data derived from a device registry; or272∙ a review of relevant retrospective data from patients previously exposed to 273the device.274275PMCF studies should have a plan describing the design and methodologies 276appropriate for addressing the stated objectives. The clinical investigation plan/study 277plan should identify and where needed justify at a minimum:278∙the study population (corresponding to the CE-mark scope);279∙inclusion/exclusion criteria;280∙rational and justification of the chosen study design including use of 281controls/control groups (where relevant; randomised or not);282∙the selection of sites and investigators;283∙study objectives and related study endpoints and statistical considerations; 284∙the number of subjects involved;285∙the duration of patient follow-up;286∙the data to be collected;287∙the analysis plan including any interim reporting where appropriate to 288ensure continuous risk management based on clinical data; and289∙procedures/criteria for early study termination;290∙ethical considerations;291∙methods of quality control of data where appropriate.292293The points above may not all apply to a retrospective data review.294295296Implementation of the PMCF study, analysis of data and conclusion(s)297The study should:298∙be executed with adequate control measures to assure compliance with the 299clinical investigation or study plan;300∙include data analysis with conclusions drawn according to the analysis plan by 301someone with appropriate expertise; and302∙have a final report with conclusions relating back to original objective(s) and 303hypothesis/hypotheses.3043053063077. The use of study data308309The data and conclusions derived from the PMCF study are used to provide clinical 310evidence for the clinical evaluation process. This may result in the need to reassess 311whether the device continues to comply with the Essential Requirements. Such 312assessment may result in corrective or preventive actions, for example changes to the 313labelling/instructions for use, changes to manufacturing processes, changes to the 314device design, or public health notifications.3153168 The role of the notified body in PMCF317When auditing the quality system of the manufacturer in the framework of one of the 318conformity assessment annexes of Directive 90/385/EEC or of Directive 93/42/EEC, 319t he Notified Body (NB) shall review the appropriateness of the manufacturer’s 320general post-market surveillance procedures and plans, including plans for PMCF, as 321relevant.322323The Notified Body shall verify that PMCF as part of the overall clinical evaluation is 324conducted by or on behalf of the manufacturer by appropriately competent assessors 325(as per section 10.3 of MEDDEV 2.7/1).326327The NB shall verify that clinical investigations conducted as part of PMCF plans are 328conducted in accordance with the relevant provisions of Annex X (as per Article 15.8 329of 93/42/EEC), related guidance and relevant standards.330331The NB shall as part of its assessment of a specific medical device5:332∙verify that the manufacturer has appropriately considered the need for 333PMCF as part of post market surveillance based on the residual risks 334including those identified from the results of the clinical evaluation and 335from the characteristics of the medical device in accordance with section 5 336of the guidance;337∙verify that PMCF is conducted when clinical evaluation was based 338exclusively on clinical data from equivalent devices for initial conformity 3395 in accordance with Annex II.4, Annex II.7, Annex III, Annex V.6 and Annex VI.6 of Directive93/42/EEC and Annex II.4, Annex II.7, Annex III and Annex V.6 of Directive 90/385/EECassessment and that PMCF addresses the residual risks identified for the 340equivalent devices;341∙assess the appropriateness of any justification presented by a manufacturer 342for not conducting a specific PMCF plan as part of post market surveillance 343and seek appropriate remedy where the justification is not valid;344∙assess the appropriateness of the proposed PMCF plan in demonstrating the 345manufacturer’s stated objectives and addressing the residual risks and issues 346of long term clinical performance and safety identified for the specific 347device;348∙verify that data gathered by the manufacturer from PMCF, whether 349favourable or unfavourable, is being used to actively update the clinical 350evaluation (as well as the risk management system);351∙consider whether, based on the specific device assessment, data obtained 352from PMCF should be transmitted to the NB between scheduled assessment 353activities (e.g. surveillance audit, recertification assessment);354∙consider an appropriate period for certification of the product in order to set 355a particular time point at which PMCF data will be assessed by the NB or 356specific conditions relating to certification for subsequent follow up. (This 357decision may be based on the residual risks, the characteristics presented in 358section 5 and the clinical evaluation presented at the time of initial 359assessment. Conditions the NB may consider could include the need for the 360manufacturer to submit interim reports between certification reviews, of the 361clinical data generated from the PMCF and post-market surveillance 362system).363364。

2023年全国医学博士英语考试真题及答案2023 National Medical Doctoral English Exam Questions and AnswersPart I: Reading ComprehensionRead the following passage and answer the questions that follow.Pain Management in Cancer PatientsPain is a common symptom experienced by cancer patients. Proper pain management is crucial to improving the quality of life for these patients. There are various methods for managing pain, including medications, physical therapy, and psychological interventions.Question 1: Why is pain management important for cancer patients?Question 2: What are some methods for managing pain in cancer patients?Question 3: How can physical therapy help in pain management?Question 4: What role do medications play in pain management for cancer patients?Part II: Listening ComprehensionListen to the following audio clip and answer the questions that follow.Audio Clip: A doctor discussing the importance of early detection in cancer patients.Question 1: Why is early detection important in cancer patients?Question 2: What are some common symptoms of cancer that patients should be aware of?Question 3: What screening tests are recommended for early detection of cancer?Question 4: How can lifestyle changes help in preventing cancer?Part III: WritingIn 250 words or less, write an essay on the importance of communication between healthcare providers and cancer patients. Discuss how effective communication can impact a patient's treatment and overall well-being.Part IV: SpeakingYou will be given a topic related to cancer treatment. Prepare a 3-minute speech on the topic and present it to the examiners.Answers:Part I: 1. Pain management is important for cancer patients because it helps improve the quality of life and overall well-being of the patients.2. Methods for managing pain in cancer patients include medications, physical therapy, and psychological interventions.3. Physical therapy can help in pain management by improving mobility, flexibility, and strength, which can reduce pain and discomfort in cancer patients.4. Medications play a crucial role in pain management for cancer patients by providing relief from pain and improving the patient's quality of life.Part II: 1. Early detection is important in cancer patients because it allows for timely treatment and improved outcomes.2. Common symptoms of cancer that patients should be aware of include unexplained weight loss, persistent fatigue, and changes in bowel or bladder habits.3. Screening tests recommended for early detection of cancer include mammograms, colonoscopies, and Pap smears.4. Lifestyle changes such as quitting smoking, maintaining a healthy weight, and getting regular exercise can help in preventing cancer.Part III: Effective communication between healthcare providers and cancer patients is crucial for ensuring the best possible treatment outcomes. When healthcare providers communicate effectively with their patients, they can better understand the patient's needs, concerns, and preferences, which can help tailor the treatment plan to meet the patient's individual needs. Effective communication can also help build trust between the healthcare provider and the patient, which is essential for a successful treatment relationship. Additionally, communication can help improve the patient's understanding of their condition, treatment options, and prognosis, which can reduce anxiety and fear associated with cancer diagnosis and treatment. Overall, effective communication can lead to better treatment outcomes, improved patient satisfaction, and a higher quality of life for cancer patients.Part IV: The topic of my speech is the importance of personalized treatment plans for cancer patients. Personalizedtreatment plans are essential for ensuring the best possible outcomes for cancer patients. By tailoring treatment plans to meet the individual needs, preferences, and characteristics of each patient, healthcare providers can maximize the effectiveness of treatment while minimizing side effects and complications. Personalized treatment plans can also help improve patient satisfaction, adherence to treatment, and overall quality of life. Ultimately, personalized treatment plans can lead to better treatment outcomes, improved survival rates, and a higher quality of life for cancer patients.。

广东省揭阳市2024-2025学年高三上学期9月月考英语试题一、阅读理解If you want to understand China but can’t afford an expensive international flight, these four books can give you a complete overview of the country.River TownRiver Town: Two Years on the Yangtze by Peter Hessler — This book is a journal of the author’s two years spent teaching English in a small town called Fuling, situated on the banks of the Yangtze River. Hessler writes about his experiences living in a foreign culture and observing the lives of the town’s residents. The book was published in 2001 and has won several awards, including the Kiriyama Prize.Deng Xiaoping and the Transformation of ChinaIt is a book that tells the story of China’s modernization. It was written by Ezra V ogel and published in 2011. The author describes how Deng Xiaoping’s policies led to significant changes in China’s economy and society. The book has received critical honors and won the Lionel Gelber Prize in 2012.The Search for Modern China by Jonathan SpenceThis book is a comprehensive history of China from the Ming dynasty to the present day. The author, a prominent scholar of Chinese history, provides a detailed analysis of the social, cultural, and political changes that have taken place in China over the past 500 years. The book was first put out in 1990 and has since been revised and updated several times. This book was the top bestseller for years.Factory Girls: From Village to City in a Changing ChinaWritten by Leslie T. Chang, this book, published in 2008, is a reportage on the lives of young women who leave their rural homes to work in factories in China’s cities. Chang, a former New York Times journalist, interviewed hundreds of factory girls to provide insight into the social and economic changes in China.1．What type of literature is River Town?A．A travel guide of Fuling.B．A personal diary.C．A science fiction.D．A reference book.2．Which statement is right about The Search for Modern China by Jonathan Spence?A．It received positive reviews.B．It was published 500 years ago.C．It was written by a history teacher.D．It has remained the same since its first publication.3．Which book is written by a reporter?A．River TownB．The Search for Modern ChinaC．Deng Xiaoping and the Transformation of ChinaD．Factory Girls: From Village to City in a Changing ChinaIt was a carefree summer day when a father, Steven Poust, was out boating on the St. John’s River with his 4-year-old daughter Abigail and 4-year-old son Chase. The children were playfully swimming near their anchored boat while their father was fishing, smiling at his kids. Suddenly, Abigail got caught in the powerful current, forcing her to release the handle on the boat. Chase let go of the boat to take hold of his little sister, but he found himself caught in the current. When Steven jumped into the water to rescue his struggling children, he was also pulled in.As they all drifted farther from the boat, the desperate father pushed his son to a safer place and tried to stick with his daughter as long as he could. However, he wore himself out later, and she drifted away from him. The father had to follow his daughter. So the responsibility to save the family was now on young Chase’s shoulders.Steven instructed his son to swim to the shore and find immediate help. Meanwhile, he would attempt to retrieve his little girl, who was continuously being pulled farther from his reach.Chase did as he was told. The young boy was swimming against the current, which made it more difficult to swim toward the shore. However, the young boy continued to swim with one thought in mind: to save his family. Chase swam as fast as he could to reach the riverbank. When he grew tired, Chase cleverly floated on his back; at times, he paddled to conserve his energy. Once he reached the shore, he raced to the closest house he could find, knocked on the door and screamed for help. The owners answered and immediately dialed 911.The Jacksonville Fire and Rescue Department responded quickly. They located the empty boat. In the water, they found kids’ shoes, a cellphone and fishing poles floating near the boat. After a 90-minute search, the search crew located the father and the daughter in the water, who had been swept a mile and a half from their abandoned boat.4．What can we know from paragraph 1?A．They had nothing to do but play near the water.B．They had a very pleasant time before the accident.C．Steven was so absorbed in fishing that he didn’t look after his kids well.D．Abigail released the handle on the boat to seek something new and exciting.5．Why did Steven count on Chase to seek for help?A．His mental strength ran out.B．His swimming skill was poorer.C．He had to try to save his daughter.D．He wanted to get Chase trained.6．Which one may NOT be the reason for their safe return?A．Chase’s intelligence and flexibility towards different situations.B．The rapid response and efficient work of relevant department.C．Abigail and Steven’s optimism and never giving up the hope of living.D．The kindness and warm heart of the room owners.7．Which of the following words can best describe Steven?A．Devoted and calm.B．Brave and generous.C．Strict and smart.D．Ambitious and honest.Sharing a bed with a pet at night is a common feature of nighttime routines in the United States. According to a 2021—2022 survey, 43 percent of pet dogs in the United States and 49 percent of pet cats sleep on their owner’s bed. When it comes to the perks of sharing your bed with your favourite furry friend, however, experts are divided.First, it’s worth noting that the majority of research on the topic of co-sleeping with pets has focused on dogs rather than cats. Mark Fierstein, an internal medicine specialist at NYUL angone Health in New York City, suggests this is because cats may want to play or even purposely wake up their owner. Rabbits or hamsters are also out of the question.A benefit of sleeping with pets is that the practice may prevent loneliness, Fierstein says.“Often, people who co-sleep with pets report an increased sense of security, companionship, and relaxation,” he notes. “For some people, the dog’s warmth, steady heartbeat, and protective nature can make sleeping with them feel safe and cozy.” This may be especially true of people who are managing trauma or post-traumatic stress disorder (PTSD). Leslie Sinn, a psychologist, says according to a survey,60% of PTSD suffers feel calm down if they wake up to see the presence of the dog.Some research suggests co-sleeping with pets may increase mid-night awakenings for people. “If the owner is a light sleeper, he or she may not do well with a dog or cat in the bedroom,” notes Fierstein. For example, he points out that a dog who snores loudly is not an ideal sleeping mate.Dogs may also show aggressive behaviour—such as biting. Allowing pets in the bedroom can also expose owners to potential allergens, like pet hair, as well as viruses that cause disease. 8．Which word can replace the underlined word “perks” in the first paragraph?A．disadvantages B．numbers C．possibility D．bonus 9．According to the text, who might be the most suitable one to sleep with a dog?A．A newborn baby.B．A survivor of an earthquake.C．An old man with a heart disease.D．A young man suffering from lack of sleep. 10．Which one is NOT the benefit to sleep with a pet?A．To relieve post-traumatic stress disorder.B．To prevent loneliness.C．To get a sense of security.D．To avoid potential allergens.11．What is the author’s attitude towards sleeping with pets?A．Objective B．Skeptical C．Ambiguous D．ApprovingNow, a new trial finds antiviral medications, when given soon after a child is diagnosed with type 1 diabetes (糖尿病), might help preserve those vital beta (β) cells.Antiviral drugs could be “used alone, or as part of combination treatment, to rescue insulin (胰岛素) — producing beta cells at diagnosis of type 1 diabetes,” said a team that presented their findings at the annual meeting of the European Association for the Study of Diabetes, in Hamburg. So-called beta cells in the pancreas (胰腺) can generate insulin. But in some cases, an uncontrolled auto-immune response causes the body to attack its own beta cells, ruining a child’scapacity to produce insulin and cause type 1 diabetes. So people with type 1 diabetes rely on insulin injections to maintain healthy blood sugar levels the rest of their lives.The researchers have been investigating the root causes of the autoimmune “malfunction” behind beta cell destruction for years, and they discovered that low-grade infections with common germs often occur in the pancreatic cells of people newly diagnosed with type l diabetes. So what if these people were given antivirals — in this case, pleconaril and ribavirin — to rid the pancreas of these infections?The new trial, led by Dr. Mynarek, sought to answer that question. The team followed96 children aged 6 to 15 who were all diagnosed with type 1 diabetes in the study. The children were randomly selected to receive either the two antiviral medicines or a placebo (无效对照剂) for six months. Mynarek’s group tracked C-peptides levels in the blood, which “mirror the insulin production in the pancreas,” implying that the higher a child’s C-peptide levels on tests, the better their pancreas was producing insulin. According to their findings, while C-peptide levels dropped a full 24% in children who received the placebo, it fell by just 11% in those who got the antivirals. That suggests the treatment helped protect the child’s pancreatic beta cells from destruction.The researchers concluded that “further studies should be done to evaluate whether antiviral treatment could delay the progression of beta-cell damage leading to clinical type l diabetes.”12．What’s the function of beta cells?A．To attack the viruses.B．To produce insulin.C．To cause diabetes.D．To absorb drugs.13．How does the new drug work for diabetes?A．To kill the germs infecting our pancreas.B．To inject insulin to our body.C．To help create more beta cells.D．To prevent common germs from attacks. 14．What does the trial find according to Mynarek’s group?A．There was no obvious difference between the two groups.B．The kids given a placebo show a higher C-peptide levels than others.C．The kids given antiviral medicines produce more insulin than others.D．The kids taking a placebo produce more insulin than others.15．Which is the best title of the text?A．The root cause of diabetes has been foundB．Beta cells could be preserved by insulinC．Autoimmune response could cause body diabetesD．Antiviral medicines could help ease Type l diabetesThe Power of “Like”Like it or love it, social media is a major part of life. Teens spend more than half of their waking hours online. And most of what they do is read and respond to posts by friends and family. Clicking on a thumbs-up is an easy way to stay in touch. 16Clicking “like” on a post can increase the number of people who see it. If other people have liked a post, new viewers will be more likely to like it too. 17 As a result, that popularity can feed on itself.What’s more, viewing one’s own posts with a lot of likes activates the reward system in their brains. Positive responses to teens’ own photos (in the form of many “likes”) tell them that their friends appreciate the material they’re posting. 18 Seeing someone else’s popular photo, however, doesn’t necessarily turn it on.19 In one 2011 study, teens doing driving task in a lab took more risks when their friends were around, which suggested that teens were changing their behavior to try to get social approval. And they make similar changes when using social media according to a research conducted last year. The research showed that popular photos might signal to teens that what’s in those photos is socially acceptable. For example, images related to alcohol may encourage teens to drink. That means that what you like online has the power to influence not just what others like, but even what they do.Joining social media can give people a sense of being in the know. However, posts may exaggerate (夸张) how well our friends and others are feeling, making them appear much happier than we are. 20A．It can also lower the viewer’s self-control.B．Teens use it to learn how to handle their social world.C．Many social media sites share more of the higher-ranked posts.D．It’s no surprise that responses from peers affect how teens behave.E．Their brains respond to those “likes” by turning on the reward center.F．And that can, inappropriately, make us feel less successful than them.G．But those “likes” can have power that goes beyond a simple connection.二、完形填空A four- year- old child in Newberry County had last been seen at about 3:00 p. m. , but she was missing later in the day. The situation took a 21 turn around 6: 00 p. m. when a hunter in the area heard the cries of the missing child. Reacting immediately, the hunter 22 an emergency call telling authorities the child's location. The operators 23 immediately, applying advanced mapping technology to locate the position. This crucial information was then 24 sent to the related Law Enforcement Division and the county's first 25 .With the location data in hand, a search team quickly 26 to the wooded area. The tireless efforts of these rescue workers ultimately 27 a heartwarming reunion. The missing four-year- old was found in the forest, safe and sound except some slight injuries. Despite her 28 experience, she was found to be in surprisingly good 29 , except her understandable tiredness, thirst and fear.The 30 rescue was the result of the 31 between different departments and the community as a whole. The Newberry County Sheriffs Office expressed their 32 for the efforts of everyone involved, including those 33 their thoughts and prayers during the search. And they showed their relief at the 34 of the little girl in the care of family. Their heroic actions will be 35 as a heartwarming success story in Newberry County in the coming years.21．A．hopeful B．disappointing C．reasonable D．challenging 22．A．received B．placed C．missed D．answered 23．A．appeared B．escaped C．arrived D．acted 24．A．optionally B．carefully C．entirely D．rapidly 25．A．rescuers B．discoverers C．operators D．survivors 26．A．adapted B．returned C．pointed D．headed 27．A．paid for B．set up C．led to D．took on 28．A．regretful B．frightening C．annoying D．shameful29．A．mind B．shape C．order D．faith 30．A．risky B．traditional C．remarkable D．joyful 31．A．respect B．balance C．cooperation D．discussion 32．A．blessing B．kindness C．concern D．gratitude 33．A．offering B．praising C．advocating D．assessing 34．A．performance B．virtue C．recovery D．courage 35．A．celebrated B．perfected C．performed D．corrected三、语法填空阅读下面短文，在空白处填入1个适当的单词或括号内单词的正确形式。

In the realm of safety and health management, the establishment of a robust safety production management system is paramount. Below is a comprehensive list of English vocabulary related to safety production management systems, accompanied by brief definitions and explanations.1. Safety Production Management System (SPMS): A structured set of policies, procedures, processes, and practices designed to ensure the health and safety of employees and the public, while minimizing risks associated with the production process.2. Occupational Health and Safety (OHS): The field of science and practice concerned with the safety, health, and well-being of people at work.3. Risk Assessment: The process of identifying, analyzing, and evaluating the risks associated with a particular activity or process.4. Hazard Identification: The process of recognizing potential sources of harm within the workplace that could cause injury or illness.5. Control Measures: Actions or measures taken to eliminate or reduce the risk of harm associated with a hazard.6. Safety Culture: The shared values, attitudes, perceptions, and practices that affect the way safety is perceived and managed within an organization.7. Safety Policy: A statement of the organization's commitment to health and safety, outlining its intentions and goals.8. Safety Regulations: Laws, standards, and codes of practice that must be followed to ensure the safety of workers and the public.9. Safety Training: Educational programs designed to inform employees about health and safety issues and to teach them how to perform their jobs safely.10. Safety Inspections: Regular checks of the workplace to identify potential hazards and ensure compliance with safety regulations.11. Incident Reporting: The process of recording and investigating accidents, injuries, and near-misses to determine their causes and prevent recurrence.12. Emergency Response Plan: A plan that outlines the actions to be taken in the event of an emergency to ensure the safety of employees and the public.13. Personal Protective Equipment (PPE): Items worn by workers toprotect themselves from potential hazards in the workplace.14. Workplace Health and Safety Act (WHS Act): Legislation that sets out the rights and duties of employers and employees regarding health and safety in the workplace.15. Health and Safety Executive (HSE): A regulatory body responsible for enforcing health and safety laws in the United Kingdom.16. Occupational Health: The branch of health that deals with the health and safety of people at work.17. Accident Investigation: The process of determining the causes of an accident and recommending measures to prevent future incidents.18. Safety Committee: A group of employees who meet regularly to discuss health and safety issues within the workplace.19. Substance Abuse: The use of harmful substances in a way that can cause harm to the user or others.20. Work-Life Balance: The balance between an employee's work responsibilities and their personal life, which can impact safety and health.21. Duty of Care: The legal obligation of an employer to ensure the health and safety of their employees.22. Management of Health and Safety at Work Regulations (MHSWR): Regulations that require employers to manage health and safety risks in the workplace.23. Safety Audit: A systematic examination of the safety management system to identify strengths and weaknesses.24. Safety Signage: Visual symbols and signs used to convey safety information and instructions.25. Subcontractor Management: The process of ensuring that subcontractors adhere to the same health and safety standards as the main contractor.26. Continuous Improvement: The ongoing process of identifying and implementing improvements to the safety management system.27. Behavior-Based Safety (BBS): A safety management approach that focuses on changing employee behaviors to reduce accidents and injuries.28. Safety Performance Indicator (SPI): A measure used to evaluate the effectiveness of safety management practices.29. Safety Promotion: Activities and initiatives aimed at raising awareness of health and safety issues within the workplace.30. Compliance: Adherence to laws, regulations, and standards.By utilizing this vocabulary, organizations can better understand and implement effective safety production management systems, ultimately creating a safer and healthier work environment.。