Evaluation of Infant Accommodation Using

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免疫细胞功能状态量化检测评估与临床应用专家共识

免疫细胞功能状态量化检测评估与临床应用专家共识

· 指南与共识·免疫细胞功能状态量化检测评估与临床应用专家共识中国医疗保健国际交流促进会肝脏移植学分会 中国医疗保健国际交流促进会肾脏移植学分会 中国医药生物技术协会生物诊断技术分会 【摘要】 免疫系统是维持机体器官功能健康和预防疾病的重要保障,免疫健康管理和疾病免疫治疗目标是恢复免疫系统的正常功能状态。

免疫学领域研究解决了如何抑制或提高免疫状态的技术性难题,随之带来亟需回答的问题是如何全面地检测和量化评估免疫状态,这是下一个挑战,目前国际上尚无成熟解决方案。

免疫状态量化检测与可视化评估对疾病防控、亚健康状态管理和疾病免疫治疗均具有重要意义。

本专家共识针对正常免疫状态定义和免疫细胞功能状态(免疫力)全面量化评估及可视化评分技术手段等问题进行了初步讨论,提出了正常免疫状态相关的基础概念和思考,探讨免疫细胞功能状态量化检测评估方向和原则,并以此为契机,推动免疫力解码以及免疫健康领域基础课题和临床试验的深入研究。

【关键词】 免疫力;免疫细胞;免疫评估;免疫治疗;健康管理【中图分类号】 R617, R392.4 【文献标志码】 A 【文章编号】 1674-7445(2024)04-0005-10Expert Consensus on quantify monitoring and assessment of immune cell function status and clinical application China International Exchange and Promotive Association for Medical and Health Care (CPAM), Society of Liver Transplantation ,Society of Kidney Transplantation; China Medicinal Biotech Association (CMBA ), Society of Biological Diagnostics.Corresponding authors: He Qiang, Beijing Chaoyang Hospital of Capital Medical University, Beijing 100020, China, Email:*******************Li Xianliang, Beijing Chaoyang Hospital of Capital Medical University, Beijing 100020, China, Email:***********************【Abstract 】 The immune system is the important guarantee for maintaining the health of organ function and preventing diseases. The goal of immune health management and immune treatment is to restore the normal function of the immune system. The technical problems of how to inhibit or enhance the immune status has been solved in the field of immunology, but how to comprehensively detect and quantitatively evaluate the immune status is still a challenge. There is no mature solution at present. The quantification detection and visualization evaluation of immune status are of great significance for disease prevention and control, sub-health status management, and immune treatment. This expert consensus has carried out preliminary discussions on the definition of normal immune status and the comprehensive quantitative evaluation and visual scoring techniques of immune cell function status (immune function), put forward the basic concepts and thinking related to normal immune status, discussed the direction and principles of quantitative detection and evaluation of immune cell function status, and taken this as an opportunity to promote the decoding of immunity and the study of basic and clinical trials in the field of immune health.【Key words 】 Immunity; Immune cell; Assessment of immunity; Immunotherapy; Health managementDOI: 10.3969/j.issn.1674-7445.2024078基金项目:国家自然科学基金(82370665);北京市自然科学基金(7232068、7232065)通信作者单位: 100020 北京,首都医科大学附属北京朝阳医院(贺强、李先亮)通信作者:贺强,Email : *******************;李先亮,Email : ***********************第 15 卷 第 4 期器官移植Vol. 15 No.4 2024 年 7 月Organ Transplantation Jul. 2024 免疫系统是人类健康的基石,大多数疾病和健康状况与免疫状态密切相关,因此免疫状态管理是健康核心问题。

评价评估的英语作文句子

评价评估的英语作文句子

1.Evaluating and assessing are essential processes in making informed decisions.评估和评价是做出明智决策的基本过程。

2.The ability to accurately evaluate a situation can significantly impact the outcome of any project.准确评估情况的能力可以显著影响任何项目的结果。

3.In order to make a fair assessment,one must consider all relevant factors and perspectives.为了做出公正的评价,必须考虑所有相关因素和视角。

4.Regular evaluations can help identify areas for improvement and enhance overall performance.定期评估可以帮助识别改进领域并提高整体表现。

5.An unbiased evaluation is crucial for maintaining the integrity of the assessment process.无偏见的评价对于保持评估过程的完整性至关重要。

6.The process of evaluation involves a systematic analysis of data to draw meaningful conclusions.评价过程涉及对数据的系统分析,以得出有意义的结论。

7.Effective assessment strategies can lead to better decisionmaking and more efficient resource allocation.有效的评估策略可以带来更好的决策制定和更高效的资源分配。

CNAS国际认证有效性论证-中英文对照版

CNAS国际认证有效性论证-中英文对照版

CNAS国际认可论证IAF是国际认可论坛IAF是国际认可论坛(International Accreditation Forum)的缩写,它是由有关国家认可机构参加的多边合作组织,成立于1993年1月,现有成员30多个,中国合格评定国家认可委员会(CNAS)是其成员单位之一,中国也是17个发起国之一。

其主要目标是协调各国认证制度,通过统一规范各成员国的审核员资格要求、培训准则及质量体系认证机构的评定和认证程序,使其在技术运作上保持一致,从而确保有效的国际互认,它在世界上包括两大组织,分别是欧洲认证认可组织(EAC)和太平洋认可合作组织(PAC)。

以认可项目等效性为基础,国际认可论坛多边承认协议签约的认可机构批准的认可,使组织持有在世界的某一地区已被认可的认证证书能在世界的任何地区被承认。

因此,被IAF多边承认协议签约认可机构认可的认证机构在管理体系、产品、服务、人员和其它类似的符合性评审项目所颁发的认证证书在国际贸易等领域均能得到世界各国承认与信任。

欧洲认证认可组织EAC欧洲认证认可组织EAC 始建于1991年,目的是在欧洲建立一个区域性的认可制度,实现对各成员国的认证机构能力的相互承认,从而达到对认证证书的相互承认。

EAC 的组成成员主要来自欧洲经济共同体和欧洲自由贸易联盟成员国的国家认可机构。

在各通过同行评定的加盟成员国认可机构间签署多边承认协议。

同行评定是指由各认可机构派代表组成联合审核组,依据ISO/CAS_CO226、ISO/CA8CO227及EN45012和 ISO/IEC48号指南对其他认可机构进行能力评审。

已签署协议的有:FINAS芬兰、RVC荷兰、NA挪威、SWEDAC瑞典、SAS瑞士、NACCB英国。

太平洋认可合作组织太平洋认可合作组织(Pacific Accreditation Cooperation, 英文缩写PAC),是由亚太经济合作组织(APEC)成员经济体的认证机构的认可机构或类似合格评定机构的认可机构及利益相关方组成的协会。

英语作文-如何评估医学护肤品制造行业规模

英语作文-如何评估医学护肤品制造行业规模

英语作文-如何评估医学护肤品制造行业规模The medical skincare industry is a burgeoning field that intersects healthcare and beauty, encompassing a wide range of products designed to maintain skin health and treat various skin conditions. Evaluating the scale of this industry requires a multifaceted approach, considering factors such as market size, growth trends, consumer demographics, and technological advancements.Market Size and Growth Trends。

To assess the market size, one can start by examining the revenue generated from the sale of medical skincare products. This includes over-the-counter items, prescription-based treatments, and professional services offered by dermatologists and aestheticians. The industry has seen a steady increase in demand, attributed to a growing awareness of skin health and the aging population seeking anti-aging solutions.Consumer Demographics。

非典型精神病药物超适应症用药

非典型精神病药物超适应症用药

Comparative Effectiveness ReviewNumber 6Efficacy and Comparative Effectiveness of Off-Label Use of Atypical AntipsychoticsThis report is based on research conducted by the Southern California/RAND Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0003). The findings and conclusions in this document are those of the author(s), who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of the Agency for Healthcare Research and Quality or of the U.S. Department of Health and Human Services.This report is intended as a reference and not as a substitute for clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information.This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.Comparative Effectiveness ReviewNumber 6Efficacy and Comparative Effectiveness ofOff-Label Use of Atypical AntipsychoticsPrepared for:Agency for Healthcare Research and QualityU.S. Department of Health and Human Services540 Gaither RoadRockville, MD 20850Contract No. 290-02-0003Prepared by:Southern California/RAND Evidence-based Practice CenterInvestigatorsPaul Shekelle, M.D., Ph.D. Lara Hilton, B.A.Director Programmer/Analyst Margaret Maglione, M.P.P. Annie Zhou, M.S.Project Manager/Policy Analyst StatisticianSteven Bagley, M.D., M.S. Susan Chen, B.A.Content Expert/Physician Reviewer Staff AssistantMarika Suttorp, M.S. Peter Glassman, M.B., B.S., M.Sc.Benefits ManagementStatistician PharmacyWalter A. Mojica, M.D., M.P.H. ExpertPhysician Reviewer Sydne Newberry, Ph.D.Jason Carter, B.A. Medical EditorCony Rolón, B.A.Literature Database ManagersAHRQ Publication No. 07-EHC003-EFJanuary 2007This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.Suggested citation:Shekelle P, Maglione M, Bagley S, Suttorp M, Mojica WA, Carter J, Rolon C, Hilton L, Zhou A, Chen S, Glassman P. Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics. Comparative Effectiveness Review No. 6. (Prepared by the Southern California/RAND Evidence-based Practice Center under Contract No. 290-02-0003.)Rockville, MD: Agency for Healthcare Research and Quality. January 2007. Available at: /reports/final.cfm.PrefaceThe Agency for Healthcare Research and Quality (AHRQ) conducts the Effective Health Care Program as part of its mission to organize knowledge and make it available to inform decisions about health care. As part of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, Congress directed AHRQ to conduct and support research on the comparative outcomes, clinical effectiveness, and appropriateness of pharmaceuticals, devices, and health care services to meet the needs of Medicare, Medicaid, and the State Children’s Health Insurance Program (SCHIP).AHRQ has an established network of Evidence-based Practice Centers (EPCs) that produce Evidence Reports/Technology Assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care. The EPCs now lend their expertise to the Effective Health Care Program by conducting Comparative Effectiveness Reviews of medications, devices, and other relevant interventions, including strategies for how these items and services can best be organized, managed, and delivered.Systematic reviews are the building blocks underlying evidence-based practice; they focus attention on the strengths and limits of evidence from research studies about the effectiveness and safety of a clinical intervention. In the context of developing recommendations for practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of the intervention are based on strong evidence from clinical studies. For more information about systematic reviews, see/reference/purpose.cfm.AHRQ expects that Comparative Effectiveness Reviews will be helpful to health plans, providers, purchasers, government programs, and the health care system as a whole. In addition, AHRQ is committed to presenting information in different formats so that consumers who make decisions about their own and their family’s health can benefit from the evidence. Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the Web site () to see draft research questions and reports or to join an e-mail list to learn about new program products and opportunities for input. Comparative Effectiveness Reviews will be updated regularly.AcknowledgmentsWe would like to thank the Effective Health Care Scientific Resource Center, located at Oregon Health & Science University, for assisting in communicating with stakeholders and ensuring consistency of methods and format.We would like to acknowledge Di Valentine, J.D., Catherine Cruz, B.A., and Rena Garland, B.A., for assistance in abstraction of adverse events data.Technical Expert PanelMark S. Bauer, M.D., Brown University, Providence Veterans Affairs Medical Center, Providence, RIBarbara Curtis, R.N., M.S.N., Washington State Department of Corrections, Olympia, WACarol Eisen, L.A. County Department of Mental Health, Los Angeles, CABruce Kagan, M.D., Ph.D., UCLA Psychiatry and Biobehavioral Science – Neuropsychiatric Institute, Los Angeles, CAJamie Mai, Pharm.D., Office of the Medical Director, Tumwater, WAAlexander L. Miller, M.D., University of Texas, Department of Psychiatry, Health Science Center at San Antonio, San Antonio, TXAdelaide S. Robb, M.D., Children’s National Medical Center, Department of Psychiatry, Washington, DCCharles Schulz, M.D., University of Minnesota, Department of Psychiatry, Minneapolis, MNSarah J. Spence, M.D., Ph.D., UCLA, Autism Evaluation Clinic, Los Angeles, CA David Sultzer, M.D., UCLA and VA Greater L.A. Healthcare System, Department. of Psychiatry and Biobehavioral Sciences, Los Angeles, CAAHRQ ContactsBeth A. Collins-Sharp, Ph.D., R.N. Margaret Coopey, M.P.S., M.G.A., R.N. Director Task Order OfficerEvidence-based Practice Center Program Evidence-based Practice Center Program Center for Outcomes and Evidence Center for Outcomes and Evidence Agency for Healthcare Research and Agency for Healthcare Research and Quality Quality Rockville, MDRockville,MDContentsExecutive Summary (1)Introduction (11)Background (11)Scope and Key Questions (15)Methods (17)Topic Development (17)Search Strategy (17)Technical Expert Panel (18)Study Selection (18)Data Abstraction (18)Adverse Events (20)Quality Assessment (20)Applicability (21)Rating the Body of Evidence (21)Data Synthesis (22)Peer Review (24)Results (25)Literature Flow (25)Key Question 1: What are the leading off-label uses of antipsychotics in the literature? (28)Key Question 2: What does the evidence show regarding the effectiveness of antipsychotics for off-label indications, such as depression? How doantipsychotic medications compare with other drugs for treating off-labelindications? (28)Dementia (28)Depression (32)Obsessive-Compulsive Disorder (37)Posttraumatic Stress Disorder (40)Personality Disorders (43)Tourette’s Syndrome (47)Autism (50)Sensitivity Analysis (51)Publication Bias (51)Key Question 3: What subset of the population would potentially benefit from off-label uses? (52)Key Question 4: What are the potential adverse effects and/or complicationsinvolved with off-label antipsychotic prescribing? (52)Key Question 5: What is the appropriate dose and time limit for off-label indications? (62)Summary and Discussion (63)Limitations (63)Conclusions (64)Future Research (69)References (71)TablesTable 1. Efficacy outcomes abstracted (19)Table 2. Pooled results of placebo-controlled trials of atypical antipsychotics for patients with dementia and behavioral disturbances or agitation (29)Table 3. Trials of atypical antipsychotics as augmentation therapy for major depression (33)Table 4. Placebo-controlled trials of atypical antipsychotics as augmentation for obsessive compulsive disorder (39)Table 5. Posttraumatic Stress Disorder (42)Table 6. Personality Disorders (46)Table 7. Tourette’s Syndrome (49)Table 8. Cardiovascular adverse events among dementia patients – Atypical Antipsychotics Compared to Placebo (55)Table 9. Neurological adverse events among dementia patients – Atypical Antipsychotics Compared to Placebo (55)Table 10. Urinary adverse events among dementia patients – Atypical Antipsychotics Compared to Placebo (56)Table 11. Summary of Evidence – Efficacy (65)Table 12. Summary of adverse event and safety findings for which there is moderate or strong evidence (67)FiguresFigure 1. Literature flow (26)Figure 2. Pooled analysis of the effect of atypical antipsychotic medications versus placebo on “response” in patients with obsessive compulsive disorder (40)AppendixesAppendix A. Exact Search StringsAppendix B. Data Collection FormsAppendix C. Evidence and Quality TablesAppendix D. Excluded ArticlesAppendix E. Adverse Event AnalysisEfficacy and Comparative Effectiveness of Off-Label Use of Atypical AntipsychoticsExecutive SummaryThe Effective Health Care Program was initiated in 2005 to provide valid evidence about the comparative effectiveness of different medical interventions. The object is to help consumers, health care providers, and others in making informed choices among treatment alternatives. Through its Comparative Effectiveness Reviews, the program supports systematic appraisals of existing scientific evidence regarding treatments for high-priority health conditions. It also promotes and generates new scientific evidence by identifying gaps in existing scientific evidence and supporting new research. The program puts special emphasis on translating findings into a variety of useful formats for different stakeholders, including consumers.The full report and this summary are available at/reports/final.cfmBackgroundolanzapine, quetiapine, risperidone, and ziprasidone are atypical antipsychotics Aripiprazole,approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia and bipolar disorder. These drugs have been studied for off-label use in the following conditions: dementia and severe geriatric agitation, depression, obsessive-compulsive disorder, posttraumatic stress disorder, and personality disorders. The atypicals have also been studied for the management of Tourette’s syndrome and autism in children. The purpose of this report is to review the scientific evidence on the safety and effectiveness of such off-label uses.The Key Questions were:Key Question 1. What are the leading off-label uses of atypical antipsychotics in theliterature?Key Question 2. What does the evidence show regarding the effectiveness of atypicalantipsychotics for off-label indications, such as depression? How do atypical antipsychotic medications compare with other drugs for treating off-label indications?Key Question 3. What subset of the population would potentially benefit from off-label uses?Key Question 4. What are the potential adverse effects and/or complications involved with off-label prescribing of atypical antipsychotics?Key Question 5. What are the appropriate dose and time limit for off-label indications?ConclusionsEvidence on the efficacy of off-label use of atypical antipsychotics is summarized in Table A. Table B summarizes findings on adverse events and safety.Leading off-label uses of atypical antipsychotics•The most common off-label uses of atypical antipsychotics found in the literature were treatment of depression, obsessive-compulsive disorder, posttraumatic stress disorder,personality disorders, Tourette's syndrome, autism, and agitation in dementia. In October 2006, the FDA approved risperidone for the treatment of autism.Effectiveness and comparison with other drugsDementia-agitation and behavioral disorders• A recent meta-analysis of 15 placebo-controlled trials found a small but statistically significant benefit for risperidone and aripiprazole on agitation and psychosis outcomes.The clinical benefits must be balanced against side effects and potential harms. See“Potential adverse effects and complications” section.•Evidence from this meta-analysis shows a trend toward effectiveness of olanzapine for psychosis; results did not reach statistical significance. The authors found three studies of quetiapine; they were too dissimilar in their design and the outcomes studied to pool.• A large head-to-head placebo controlled trial (Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease; CATIE-AD) concluded there were nodifferences in time to discontinuation of medication between risperidone, olanzapine,quetiapine, and placebo. Efficacy outcomes favored risperidone and olanzapine, andtolerability outcomes favored quetiapine and placebo.•We found no studies of ziprasidone for treatment of agitation and behavioral disorders in patients with dementia.•Strength of evidence = moderate for risperidone, olanzapine, and quetiapine; low for aripiprazole.Depression•We identified seven trials where atypical antipsychotics were used to augment serotonin reuptake inhibitor (SRI) treatment in patients with initial poor response to therapy, twostudies in patients with depression with psychotic features, and four trials in patients with depression with bipolar disorder.•For SRI-resistant patients with major depressive disorder, combination therapy with an atypical antipsychotic plus an SRI antidepressant is not more effective than an SRI alone at 8 weeks.•In two trials enrolling patients with major depressive disorder with psychotic features, olanzapine and olanzapine plus fluoxetine were compared with placebo for 8 weeks.Neither trial indicated a benefit for olanzapine alone. In one trial, the combination group had significantly better outcomes than placebo or olanzapine alone, but the contribution of olanzapine cannot be determined, as the trial lacked a fluoxetine-only comparison arm.•For bipolar depression, olanzapine and quetiapine were superior to placebo in one study for each drug, but data are conflicting in two other studies that compared atypicalantipsychotics to conventional treatment.•We found no studies of aripiprazole for depression.•Strength of evidence = moderate strength of evidence that olanzapine, whether used as monotherapy or augmentation, does not improve outcomes at 8 weeks in SRI-resistantdepression; low strength of evidence for all atypical antipsychotics for other depression indications due to small studies, inconsistent findings, or lack of comparisons to usualtreatment.Obsessive-compulsive disorder (OCD)•We identified 12 trials of risperidone, olanzapine, and quetiapine used as augmentation therapy in patients with OCD who were resistant to standard treatment.•Nine trials were sufficiently similar clinically to pool. Atypical antipsychotics have a clinically important benefit (measured by the Yale-Brown Obsessive-Compulsive Scale) when used as augmentation therapy for patients who fail to adequately respond to SRItherapy. Overall, patients taking atypical antipsychotics were 2.66 times as likely to“respond” as placebo patients (95-percent confidence interval (CI): 1.75 to 4.03).Relative risk of “responding” was 2.74 (95-percent CI: 1.50 to 5.01) for augmentationwith quetiapine and 5.45 (95-percent CI: 1.73 to 17.20) for augmentation withrisperidone. There were too few studies of olanzapine augmentation to permit separatepooling of this drug.•We found no trials of ziprasidone or aripiprazole for obsessive-compulsive disorder.•Strength of evidence = moderate for risperidone and quetiapine; low for olanzapine due to sparse and inconsistent results.Posttraumatic stress disorder (PTSD)•We found four trials of risperidone and two trials of olanzapine of at least 6 weeks duration in patients with PTSD.•There were three trials enrolling men with combat-related PTSD; these showed a benefit in sleep quality, depression, anxiety, and overall symptoms when risperidone orolanzapine was used to augment therapy with antidepressants or other psychotropicmedication.•There were three trials of olanzapine or risperidone as monotherapy for women with PTSD; the evidence was inconclusive regarding efficacy.•We found no studies of quetiapine, ziprasidone, or aripiprazole for PTSD.•Strength of evidence = low for risperidone and olanzapine for combat-related PTSD due to sparse data; very low for risperidone or olanzapine for treating non-combat-relatedPTSD.Personality disorders•We identified five trials of atypical antipsychotic medications as treatment for borderline personality disorder and one trial as treatment for schizotypal personality disorder.•Three randomized controlled trials (RCTs), each with no more than 60 subjects, provide evidence that olanzapine is more effective than placebo and may be more effective than fluoxetine in treating borderline personality disorder.•The benefit of adding olanzapine to dialectical therapy for borderline personality disorder was small.•Olanzapine caused significant weight gain in all studies.•Risperidone was more effective than placebo for the treatment of schizotypal personality disorder in one small 9-week trial.•Aripiprazole was more effective than placebo for the treatment of borderline personality in one small 8-week trial.•We found no studies of quetiapine or ziprasidone for personality disorders.•Strength of evidence = very low due to small effects, small size of studies, and limitations of trial quality (e.g., high loss to followup).Tourette’s syndrome•We found four trials of risperidone and one of ziprasidone for treatment of Tourette’s syndrome.•Risperidone was more effective than placebo in one small trial, and it was at least as effective as pimozide or clonidine for 8 to 12 weeks of therapy in the three remainingtrials.•The one available study of ziprasidone showed variable effectiveness compared to placebo.•We found no studies of olanzapine, quetiapine, or aripiprazole for Tourette’s syndrome.•Strength of evidence = low for risperidone; very low for ziprasidone.Autism•Just before this report was published, the FDA approved risperidone for use in autism.•Two trials of 8 weeks duration support the superiority of risperidone over placebo in improving serious behavioral problems in children with autism. The first trial showed agreater effect for risperidone than placebo (57-percent decrease vs. 14-percent decrease in the irritability subscale of the Aberrant Behavior Checklist). In the second trial, morerisperidone-treated than placebo-treated children improved on that subscale (65 percentvs. 31 percent).•We found no trials of olanzapine, quetiapine, ziprasidone, or aripiprazole for this indication.•Strength of evidence = low.Population that would benefit most from atypical antipsychotics •There was insufficient information to answer this question. It is included as a topic for future research.Potential adverse effects and complications•There is high-quality evidence that olanzapine patients are more likely to report weight gain than those taking placebo, other atypical antipsychotics, or conventionalantipsychotics. In two pooled RCTs of dementia patients, olanzapine users were 6.12times more likely to report weight gain than placebo users. In a head-to-head trial ofdementia patients, olanzapine users were 2.98 times more likely to gain weight thanrisperidone patients. In the CATIE trial, elderly patients with dementia who were treatedwith olanzapine, quetiapine, or risperidone averaged a monthly weight gain of 1.0, 0.7, and 0.4 pounds while on treatment, compared to a weight loss among placebo-treated patients of 0.9 pounds per month. Even greater weight gain relative to placebo has been reported in trials of non-elderly adults.•In two pooled RCTs for depression with psychotic features, olanzapine patients were 2.59 times as likely as those taking conventional antipsychotics to report weight gain.•In a recently published meta-analysis of 15 dementia treatment trials, death occurred in3.5 percent of patients randomized to receive atypical antipsychotics vs. 2.3 percent ofpatients randomized to receive placebo. The odds ratio for death was 1.54, with a 95-percent CI of 1.06 to 2.23. The difference in risk for death was small but statistically significant. Sensitivity analyses did not show evidence for differential risks forindividual atypical antipsychotics. Recent data from the DEcIDE (Developing Evidence to Inform Decisions about Effectiveness) Network suggest that conventionalantipsychotics are also associated with an increased risk of death in elderly patients with dementia, compared to placebo.•In another recently published meta-analysis of six trials of olanzapine in dementia patients, differences in mortality between olanzapine and risperidone were notstatistically significant, nor were differences between olanzapine and conventionalantipsychotics.•In our pooled analysis of three RCTs of elderly patients with dementia, risperidone was associated with increased odds of cerebrovascular accident compared to placebo (odds ratio (OR): 3.88; 95-percent CI: 1.49 to 11.91). This risk was equivalent to 1 additional stroke for every 31 patients treated in this patient population (i.e., number needed to harm of 31). The manufacturers of risperidone pooled four RCTs and found thatcerebrovascular adverse events were twice as common in dementia patients treated with risperidone as in the placebo patients.•In a separate industry-sponsored analysis of five RCTs of olanzapine in elderly dementia patients, the incidence of cerebrovascular adverse events was three times higher inolanzapine patients than in placebo patients.•We pooled three aripiprazole trials and four risperidone trials that reported extrapyramidal side effects (EPS) in elderly dementia patients. Both drugs wereassociated with an increase in EPS (OR: 2.53 and 2.82, respectively) compared toplacebo. The number needed to harm was 16 for aripiprazole and 13 for risperidone.•Ziprasidone was associated with an increase in EPS when compared to placebo in a pooled analysis of adults with depression, PTSD, or personality disorders (OR: 3.32; 95-percent CI: 1.12 to 13.41).•In the CATIE trial, risperidone, quetiapine, and olanzapine were each more likely to cause sedation than placebo (15-24 percent vs. 5 percent), while olanzapine andrisperidone were more likely to cause extrapyramidal signs than quetiapine or placebo(12 percent vs. 1-2 percent). Cognitive disturbance and psychotic symptoms were morecommon in olanzapine-treated patients than in the other groups (5 percent vs. 0-1percent).•There is insufficient evidence to compare atypical with conventional antipsychotics regarding EPS or tardive dyskinesia in patients with off-label indications.•Risperidone was associated with increased weight gain compared to placebo in our pooled analyses of three trials in children/adolescents. Mean weight gain in therisperidone groups ranged from 2.1 kg to 3.9 kg per study. Odds were also higher forgastrointestinal problems, increased salivation, fatigue, EPS, and sedation among theseyoung risperidone patients.•Compared to placebo, all atypicals were associated with sedation in multiple pooled analyses for all psychiatric conditions studied.Appropriate dose and time limit•There was insufficient information to answer this question. It is a topic for future research.Remaining IssuesMore research about how to safely treat agitation in dementia is urgently needed. The CATIE-AD study has substantially added to our knowledge, but more information is still necessary. We make this statement based on the prevalence of the condition and uncertainty about the balance between risks and benefits in these patients. While the increased risk of death in elderly dementia patients treated with atypical antipsychotics was small, the demonstrable benefits in the RCTs were also small. Information is needed on how the risk compares to risks for other treatments.An established framework for evaluating the relevance, generalizability, and applicability of research includes assessing the participation rate, intended target population, representativeness of the setting, and representativeness of the individuals, along with information about implementation and assessment of outcomes. As these data are reported rarely in the studies we reviewed, conclusions about applicability are necessarily weak. In many cases, enrollment criteria for these trials were highly selective (for example, requiring an open-label run-in period). Such highly selective criteria may increase the likelihood of benefit and decrease the likelihood of adverse events. At best, we judge these results to be only modestly applicable to the patients seen in typical office-based care.With few exceptions, there is insufficient high-grade evidence to reach conclusions about the efficacy of atypical antipsychotic medications for any of the off-label indications, either vs. placebo or vs. active therapy.More head-to-head trials comparing atypical antipsychotics are needed for off-label indications other than dementia.IntroductionBackgroundAntipsychotic medications, widely used for the treatment of schizophrenia and other psychotic disorders, are commonly divided into two classes, reflecting two waves of historical development. The conventional antipsychotics--also called typical antipsychotics, conventional neuroleptics, or dopamine antagonists--first appeared in the 1950s and continued to evolve over subsequent decades, starting with chlorpromazine (Thorazine), and were the first successful pharmacologic treatment for primary psychotic disorders, such as schizophrenia. While they provide treatment for psychotic symptoms - for example reducing the intensity and frequency of auditory hallucinations and delusional beliefs - they also commonly produce movement abnormalities, both acutely and during chronic treatment, arising from the drugs’ effects on the neurotransmitter dopamine. These side effects often require additional medications, and in some cases, necessitate antipsychotic dose reduction or discontinuation. Such motor system problems spurred the development of the second generation of antipsychotics, which have come to be known as the “atypical antipsychotics.”Currently, the U.S. Food and Drug Administration (FDA)-approved atypical antipsychotics are aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Off-label use of the atypical antipsychotics has been reported for the following conditions: dementia and severe geriatric agitation, depression, obsessive-compulsive disorder, posttraumatic stress disorder, and personality disorders. The purpose of this Evidence Report is to review the evidence supporting such off-label uses of these agents. We were also asked to study the use of the atypical antipsychotics for the management of Tourette’s Syndrome and autism in children. The medications considered in this report are those listed above; however, we have excluded clozapine, which has been associated with a potentially fatal disorder of bone-marrow suppression and requires frequent blood tests for safety monitoring. Because of these restrictions, it is rarely used except for schizophrenia that has proven refractive to other treatment. Dementia and Severe Geriatric AgitationDementia is a disorder of acquired deficits in more than one domain of cognitive functioning. These domains are memory, language production and understanding, naming and recognition, skilled motor activity, and planning and executive functioning. The most common dementias – Alzheimer’s and vascular dementia - are distinguished by their cause. Alzheimer’s dementia occurs with an insidious onset and continues on a degenerative course to death after 8 to10 years; the intervening years are marked by significant disturbances of cognitive functioning and behavior, with severe debilitation in the ability to provide self-care. Vascular dementia refers to deficits of cognitive functioning that occur following either a cerebrovascular event – a stroke – leading to a macrovascular dementia, or, alternatively, more diffusely located changes in the smaller blood vessels, leading to a microvascular dementia. These (and other) dementia types commonly co-occur. Psychotic symptoms are frequent among dementia patients and include。

2012 EUSOMA推荐建议:年轻女性乳腺癌患者的管理 欧洲乳腺癌专科学会(EUSOMA)

2012 EUSOMA推荐建议:年轻女性乳腺癌患者的管理 欧洲乳腺癌专科学会(EUSOMA)

Position PaperThe European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancerFatima Cardoso a ,b ,⇑,Sibylle Loibl c ,Olivia Pagani d ,Alessandra Graziottin e ,Pietro Panizza f ,Laura Martincich g ,Oreste Gentilini h ,Fedro Peccatori i ,Alain Fourquet j ,Suzette Delaloge k ,Lorenza Marotti l ,Fre´de ´rique Penault-Llorca m ,Anna Maria Kotti-Kitromilidou n ,Alan Rodger o ,Nadia Harbeck paBreast Unit,Champalimaud Cancer Center,Lisbon,Portugal bEuropean School of Oncology,Milan,Italy cDepartment of Medicine and Research,German Breast Group,Neu-Isenburg,Frankfurt,Germany dBreast Unit of Southern Switzerland,Bellinzona,Switzerland eCenter of Gynecology and Medical Sexology,H.San Raffaele Resnati,Milan,Italy fUnit of Radiology 1,Fondazione IRCCS,Istituto Nazionale Tumori,Milan,Italy gDepartment of Diagnostic Imaging,Institute for Cancer Reseach and Treatment,Fondazione Piemontese per l’Oncologia,Candiolo (Turin),Italy hDivision of Breast Surgery,European Institute of Oncology,Milan,Italy iDepartment of Medicine,European Institute of Oncology,Milan,Italy jDepartment of Radiation Oncology,Institut Curie,Paris,France kDepartment of Medical Oncology,Institut Gustave Roussy,Villejuif,France lEUSOMA,Florence,Italy mDepartment of Pathology,Centre Jean Perrin,Clemont-Ferrand Cedex,France nEuropa Donna,Cyprus oRadiation Oncology,Glasgow,Scotland,UK pBreast Center,Department of Obstetrics and Gynaecology,University of Munich,GermanyAvailable online 29October 2012KEYWORDS Guidelines Breast cancer Young women Treatment Fertility PregnancyAbstractEUSOMA (The European Society of Breast Cancer Specialists)is committed towriting recommendations on different topics of breast cancer care which can be easily adopted and used by health professionals dedicated to the care of patients with breast cancer in their daily practice.In 2011,EUSOMA identified the management of young women with breast cancer as one of the hot topics for which a consensus among European experts was needed.Therefore,the society recently organised a workshop to define such recommendations.Thirteen experts from the different disciplines met for two days to discuss the topic.This international and0959-8049/$-see front matter Ó2012Elsevier Ltd.All rights reserved./10.1016/j.ejca.2012.10.004⇑Corresponding author:Address:Breast Cancer Unit,Champalimaud Cancer Center,Av.De Brası´lia –Doca de Pedrouc ßos,1400-048Lisbon,Portugal.Tel.:+351210480004;fax:+351213568169.E-mail addresses:fatimacardoso@fundacaochampalimaud.pt ,fatima.cardoso@bordet.be (F.Cardoso).multidisciplinary panel thoroughly reviewed the literature in order to prepare evidence-based recommendations.During the meeting,two working groups were set up to discuss in detail diagnosis and loco-regional and systemic treatments,including both group aspects of psychol-ogy and sexuality.The conclusions reached by the working groups were then discussed in a plenary session to reach panel consensus.Whenever possible,a measure of the level of evi-dence(LoE)from1(the highest)to4(the lowest)degree,based on the methodology proposed by the US Agency for Healthcare Research and Quality(AHRQ),was assigned to each rec-ommendation.The present manuscript presents the recommendations of this consensus group for the man-agement of young women with breast cancer in daily clinical practice.Ó2012Elsevier Ltd.All rights reserved.1.General introduction and methodsFor the purpose of these guidelines,The European Society of Breast Cancer Specialists(EUSOMA)work-ing group decided to define“young women”as women under the age of40.We acknowledge that both biology and endocrine milieu are a continuum and that age group definition will always be arbitrary.However, women under the age of40have specific issues related to fertility preservation,pregnancy and lactation that deserve a different approach and management from slightly older pre-and peri-menopausal women.The risk of breast cancer is age-dependent.The probability of developing breast cancer is equal to 0.04%per year for average risk women between age 30and39and increases to>10%per year in those over 80years.1Breast cancer in women under40years is not a com-mon condition(Fig.1).However,a dramatic increase in the number of breast cancers diagnosed in pre-menopausal women has been reported in several coun-tries.In the United States,5.5%of breast cancers occur in women younger than the age of40years.2 Approximately one in forty women diagnosed with early breast cancer is very young(<35years).Breast cancer in young women is associated with a positive family history and gene mutations more frequently than in older women.2In addition,the working group also decided to focus on recommendations specific for this age group.Yet,we still want to emphasise those general recommendations that do not necessarily differ with age but are particu-larly important for young women.We,thus,want to avoid over-and under-treatment based more on physi-cians’concern than on actual evidence.During the review of all available evidence,we rea-lised that there are many issues regarding the manage-ment of young women for which evidence is lacking. Such issues are,therefore,highlighted in the article as research priorities.Issues of body image,sexuality,fertility and lactation must be discussed with young women with breast can-cer.These issues are of course important for women of all ages albeit the actual importance is weighted on an individual basis that is not necessarily related to age. Issues of fertility and lactation are,by definition,related to age and menopausal status even outside breastAge Annual incidence/100 000 women<200.120-24 1.425-298.130-3424.835-3958.440-44116.145-49198.5(a)(b)3356 F.Cardoso et al./European Journal of Cancer48(2012)3355–3377cancer.In particular,fertility issues must be discussed before the start of any type of anticancer treatment, since treatment consequences may be irreversible and there is a predefined time schedule specific to each fertil-ity preservation intervention that may also impact on anticancer therapy.All these issues must continue to be discussed throughout follow-up.Age has been shown in several studies to be an inde-pendent adverse prognostic factor for women with a diagnosis of breast cancer.3–8There is a continuous lin-ear effect,with a4%decrease in distant recurrence and 6%in local recurrence for every additional year of age.9There are also data showing a higher risk of con-tralateral BC in young women,10in particular in BRCA mutation carriers11and increased mortality in young women.12While some preliminary studies suggest that the dis-tribution of the different biological subtypes of breast cancer is different in young women with a higher preva-lence of triple negative and Human Epidermal Growth Factor Receptor2(HER-2)+disease7,8,a clear molecu-lar characterisation of breast cancer in these patients is lacking and is a RESEARCH PRIORITY.In addition, it should be recognised that there are some rare histolog-ical subtypes such as“juvenile secretory adenocarci-noma”that are more frequent in the very young women.Despite the fact that they are triple negative their prognosis is good.2.Screening,diagnosis and staging2.1.General considerationsThe aim of this section of the paper is to evaluate the currently recognised radiological imaging modalities (mammography,ultrasound and magnetic resonance) for diagnosis and staging of breast cancer.To date,there is no evidence in the literature suggesting clinical utility of other emerging diagnostic tools in both diagnosis and local staging of breast cancer.For young women,due to the intrinsic difficulties in diagnosis,imaging evaluation of breast abnormalities should be done by experienced professionals,preferably in departments of radiology with experience on breast diagnostic and interventional procedures.In addition, when suspicious breast abnormalities are identified,fast diagnosis is the highest priority.With regard to the tim-ing of imaging,if not urgent,mammography should preferably be performed during thefirst2weeks of the menstrual cycle while ultrasound can be performed at any time point.Magnetic resonance imaging(MRI) should be performed in the second week of the men-strual cycle(day6–13counting from thefirst day of bleeding),and should follow the recommended technical requirements.13It should also be noted that imaging is not influenced by hormonal contraception.2.2.Screening2.2.1.Women at average riskAt the present time,mammography is the diagnostic modality of choice for screening for early breast cancer.14,15The sensitivity of mammography in women over the age of50has been estimated to be around 85%(range68%to>90%)while it was reported to be lower(range62–76%)in women between40and 49years.16The advent of full-field digital mammogra-phy suggests a further positive clinical impact on early detection of breast cancer.17Studies comparing the diag-nostic performance of full-field digital mammography with screen-film mammography in a corporate screen-ing,showed a significantly higher cancer detection rate and positive predictive value for full-field digital mam-mography,especially in women under the age of50.18 Results from randomised clinical trials(RCTs)showed that screening mammography reduces the number of deaths from breast cancer in women between40and 74years of age.19,20A recent systematic analysis of major RCTs showed that screening mammography pro-vides an average mortality reduction of about19%with its major impact(mortality reduction of30%)in the age group of49–59years.21Screening programmes must consider the incidence of the disease,the performance of the diagnostic tests as well as the costs to both patients and society.The low incidence of sporadic breast cancer before the age of40and the suboptimal performance of diagnostic modalities in these women justify the absence of trials investigating not only the efficacy but also the feasibility of breast cancer screening programmes in women under40years of age.In addi-tion,studies conducted in women under the age of 40years not only failed to show a benefit from regular screening mammography but also demonstrated high recall rates,high rates of additional imaging and low cancer detection rates.22The efficacy of a baseline mam-mogram for women at average risk at the age of35–40years to provide a comparison image available when regular screening begins at the age of40years or older, was tested in the past,yet there was no sign of benefit from such a baseline screening.23Breast augmentation is increasingly performed in young women for cosmetic purposes.The presence of breast implants does not represent a risk factor.Several case control and cohort studies have not shown an increased risk for breast cancer due to augmentation mammoplasty.24To date no studies have investigated screening programmes or imaging surveillance in aesthet-ically augmented women under40years who are at aver-age risk.There are some data suggesting that the presence of implants may lead to a loss of28–49%of the breast on mammographic view.25The sensitivity of a screening mammography in asymptomatic women is lower in women with breast augmentation in comparison to thoseF.Cardoso et al./European Journal of Cancer48(2012)3355–33773357without(45.0%versus66.8%);yet,the specificity is slightly higher in women with augmentation(97.7% versus96.7%).26It was reported that–at time of diagno-sis–breast cancers are more frequently palpable in augmented women than in those without implants(75% versus54%).27This observation raises the hypothesis that the presence of breast implants may lead to a delayed diagnosis with all its consequences.Young women plan-ning to have a breast augmentation surgery should be specifically informed about this issue.However,pub-lished studies confirmed that prognosis,disease-free time and survival rates are similar between augmented and non-augmented women with breast cancer.26–28 No evidence exists for recommending periodic contrast-enhanced MRI in women at average risk,both with or without cosmetic breast implants.13The avail-able evidence for the benefit of breast self examination (BSE)is limited and mostly relates to increased breast health awareness.14,152.2.1.1.In summary.Regular breast self-examination and clinical breast examination should be recommended for all the women at average risk under40years of age.Women also need to be informed about the limitations and risks of breast examination.The ideal time for breast examination is after menstruation(level of evidence (LoE)expert opinion).The panel emphasises that any new breast abnormal-ity in young women should be thoroughly investi-gated(imaging,needle biopsy),even though the incidence of breast cancer is lower in this age group, to avoid misdiagnosis and delayed diagnosis,and importantly to minimise unnecessary surgical inter-vention for non-malignant conditions.Adequate information about genetic counselling and imaging surveillance programmes should be provided to all young women with a strong family history of breast cancer(LoE expert opinion).There is no evidence to recommend regular diagnostic surveillance in augmented and non-augmented women at average risk under40years of age(LoE III).A pre-operative diagnostic check,including clinicalexamination,mammography(if the women are between age35and40years)and/or ultrasound is suggested in women at average risk under the age of40years,undergoing aesthetically breast augmen-tation(LoE expert opinion).2.2.2.High-risk womenIn2010,EUSOMA published a paper evaluating the available evidence regarding clinical value of and indica-tions for breast MRI.13This paper reported the results of all the cohort studies investigating the diagnostic performance of different imaging modalities in the surveillance of high-risk women.Because no significant modifications have occurred since that publication, we summarise these EUSOMA recommendations and refer to that particular paper for more detailed information.2.2.2.1.In summary.Women with a family history suggesting an inherited predisposition to breast cancer should have their risk assessed by an appropriately trained professional group(e.g.genetic counselling)(LoE expert opinion).If found to be at high risk(20–30%lifetime risk or greater),these women should be given oral and written information regarding their risk and the risks and ben-efits of mammography and MRI screening or alterna-tive risk-reducing interventions;if these women accept to be screened by MRI,they should be informed about screening intervals and logistics(LoE expert opinion).Lifetime risk thresholds for including women in surveillance programmes with annual MRI may be determined on the basis of regional or national consid-erations reflecting an area-specific cumulative risk in the general population,resource availability and practical feasibility(LoE expert opinion).High-risk breast screening utilising MRI should be conducted only by a nationally/regionally approved and audited service or as part of an ethically approved research study.Periodical audits should be undertaken to ensure that high sensitivity is achieved and that the early recall rate(MR imaging more frequent than annually)is less than10%,and to monitor detection rate,needle biopsy rate and interval cancers(LoE expert opinion).Annual MRI screening should be available starting at age30.Starting annual screening before age30may be discussed,such as in BRCA1or BRCA2mutation carriers(starting between age25and29years)and TP53mutation carriers(starting at age20)(LoE IIb). Annual MRI screening should be offered to:o BRCA1,BRCA2and TP53mutation carriers’.o Women at50%risk to be carriers of BRCA1, BRCA2or TP53mutation(first-degree relatives of mutation carriers)(LoE-Ib).o Women from families not tested or inconclusively tested for BRCA mutation with a20–30%lifetime risk or greater(LoE-II).o Women with prior mantle radiotherapy before age30(e.g.for Hodgkin disease),starting8years after theirtreatment(LoE III).o Women at high risk and who were already diagnosed and treated for breast cancer should be included in screening programmes including MRI(LoE-IIb).Women of any age undergoing prophylactic mastec-tomy should have a MRI examination within the 3months before surgery to screen for occult breast cancer(LoE expert opinion).3358 F.Cardoso et al./European Journal of Cancer48(2012)3355–3377Screening mammography should not be performed in high-risk women below35years as there is no evi-dence that the benefits outweigh the risks in this young age group(LoE expert opinion).In TP53mutation carriers of any age,annual mam-mography can be avoided based on the discussion of risks and benefits from radiation exposure(LoE expert opinion).Annual mammography may be considered for high-risk women starting at age35years(LoE III).If annual MRI is performed,additional screening with breast ultrasound(US)and clinical breast exam-ination(CBE)are not necessary as there is no evi-dence of any benefit added to MRI(LoE II).They are however recommended in women under35years who do not tolerate or have contraindications to MRI or gadolinium-based contrast administration (LoE expert opinion).Cases requiring workup after MRI should be initially assessed with conventional imaging–re-evaluation of mammography and targeted US(LoE II).In cases of suspiciousfindings solely detected by MRI,MR-guided biopsy localisation should be performed (LoE I).Risk factors such as prior diagnosis of invasive breast cancer or Ductal Carcinoma In Situ(DCIS),atypical ductal hyperplasia,lobular intraepithelial neoplasia, heterogeneous or dense breasts on mammography, if not associated with other risk factors,do not confer an increased risk justifying the use of screening MRI (LoE III).2.3.DiagnosisThe diagnosis of breast cancer in young women may be difficult because of dense breast tissue,lack of previ-ous routine breast screening and shorter tumour dou-bling times.For this age group,due to these intrinsic difficulties in diagnosis,imaging evaluation of breast lesions should only be done by experienced profession-als.Breast cancer in young women more frequently pre-sents with a higher disease stage and poorer prognosis than in older women.In fact,>90%of young women with breast cancer are symptomatic,but it is important to consider that most of the young women presenting with breast symptoms do not have breast cancer.Only a few studies in the literature have investigated the diagnostic performance of imaging in young women with breast symptoms.The cancer detection rate of mammography in symptomatic women under40years ranges in the literature between55%and86%.2In a ret-rospective study investigating239cases of breast cancer in women less than40years during a period of10years, Foxcroft and colleagues reported that70.8%of the sub-jects had a mammographic abnormality which was correctly classified as malignant in52.8%.Mammogra-phy was the only satisfactory imaging modality for dem-onstrating small clusters of microcalcifications.29 Houssami and colleagues retrospectively evaluated the diagnostic performance of conventional imaging in240 patients with breast cancer of whom64were under 40years.In this subgroup,the sensitivity of mammogra-phy ranged between69%and76%while the specificity was between83%and96%.30Since ultrasound is less affected by breast density,it shows a better diagnostic performance than mammogra-phy in symptomatic young patients.In the series of Fox-croft,it showed an abnormality in95.5%,which was correctly classified as benign or probably benign in 25.5%of the cases.In the study of Houssami,the breast cancer detection rate of ultrasound was84%with a spec-ificity between84%and91%.These results,associated with the potential damage from ionising radiation exposure,suggest that ultraso-nography could be the primary imaging test in symp-tomatic women younger than40years(LoE Expert Opinion).As in older women,ultrasound guided biopsy should be performed if a sonographically suspicious finding is detected.Since malignant lesions may mimic benign lesions in high-risk women,ultrasound guided biopsy should also be considered when a probably benign sonographicfinding is detected in these patients. The subsequent use of mammography should be decided on the basis of the biopsy result.If the result is positive or inconclusive,mammography is indicated to define the extent of the disease or to add further diagnostic infor-mation,respectively.If ultrasound is negative,the potential benefit of a clinical biopsy and/or mammogra-phy is related to the degree of clinical suspicion and the breast cancer prevalence.As in older women,accurate pre-surgical local stag-ing of breast cancer is required to ensure a complete excision of the disease.In the study of Foxcroft,mam-mography was unreliable for diagnosing multifocality while ultrasound was useful in the detection of other dis-ease foci.In addition,ultrasound was also more reliable in the assessment of the size of the lesion as confirmed by pathology.Thesefindings suggest that bilateral breast ultrasound,including the axilla,should be per-formed in the diagnostic workup of all breast cancer patients less than40years.The role of MRI in the preoperative setting is still controversial.MRI is recognised as the most sensitive modality both in identification and local staging of breast cancer13but shows limitations in terms of variable spec-ificity31MRI shows a better diagnostic performance in staging invasive lobular breast cancer32and in identifying contralateral disease foci.33It has been shown that MRI is more sensitive than conventional imaging in the evalu-ation of an extensive intraductal component(EIC)and DCIS without microcalcifications,both of which are more frequent in young and in high-risk women.34F.Cardoso et al./European Journal of Cancer48(2012)3355–33773359MRI also has a higher negative predictive value(97%for a lesion of P2cm)for measuring the distance between nipple/areolar complex and the lesion itself,35which is useful for planning nipple sparing mastectomy.On the other hand,the main concerns regarding MRI are its unclear impact on clinical outcome and the potential risk of surgical overtreatment.Two randomised prospective trials evaluated the impact of preoperative MRI on surgi-cal outcome.35,36In both trials,the introduction of MRI in the management of patients undergoing surgery did not lead to a reduction of re-excision rate.Moreover,in the COMICE trial35the mastectomy rate was signifi-cantly higher in the arm with MRI with respect to that without(7%versus1%).Only retrospective studies inves-tigated the impact of MRI on long-term clinical out-comes.In the study of Fischer et al.37the IBTR rate at a follow-up of40months was1.2%for the86patients who underwent pre-operative MRI with respect to6.8% for the133without pre-operative MRI.Conversely,the studies of Solin et al.38and Hwang et al.39reported no differences in IBTR rate between patients with and with-out preoperative MRI.In brief,even though MRI is the most sensitive modality in the identification of breast cancer,at present there is no evidence that detection of additional malignant foci with MRI before treatments translates into patient benefit from both surgical care and prognosis.31,40,41However,it should be taken into account that published evidence does not reflect breast cancer patients under40years.3,122.3.1.In summaryAs in older women,young women presenting with breast symptoms and a strong suspicion of breast can-cer should be evaluated by triple assessment(clinical examination,imaging and cytological/histological examination)in order to exclude or confirm a diagno-sis of cancer(LoE IIa)When a palpable abnormality is present,patients should have ultrasound followed, if required(in case of Breast Imaging-Reporting And Data System(BIRADS)3–5),by core biopsy and/orfine needle aspirate cytology(LoE IIa).The subsequent use of mammography should be based on the biopsy result(LoE expert opinion).If the result is positive or inconclusive,mammography is indicated to define the extent of disease or to add further diag-nostic information(LoE expert opinion).If the ultrasound is negative(BIRADS1–2),the ben-efit of a clinical biopsy and/or mammography is related to the degree of clinical suspicion and the breast cancer prevalence(LoE expert opinion).As in older women,a lesion considered malignant fol-lowing clinical examination,imaging or cytology alone should,where possible,have a histopathological confirmation of malignancy before any surgical proce-dure takes place.Immunohistochemical biomarkers(oestrogen and progesterone receptors status,HER-2status and proliferation(e.g.Ki67))should be mea-sured on all invasive primary breast cancers,ideally in both core biopsy and surgical specimen.As in older women,in cases of possible or scheduled pri-mary chemotherapy,immunohistochemical biomark-ers(oestrogen receptor(ER),partial response(PR), HER-2and proliferation)should be measured in the core biopsy before the beginning of medical treatment. If malignancy is diagnosed,bilateral ultrasound of the breast and axilla should be performed for local staging of the disease(LoE IIa).There is no evidence to recommend routine preoper-ative MRI in young women with breast cancer.Indi-cations for MRI are the same as for older women, including patients with newly diagnosed invasive lob-ular cancer(LoE IIa),patients at high-risk for breast cancer(LoE IIb),patients with a size discrepancy of more than1cm between mammography and ultra-sound and an expected impact on the treatment deci-sion(LoE IIb).Because of the special characteristics of young patients,multidisciplinary evaluation of the advantages and disadvantages of pre-operative MRI taking into account the planned surgical approach, is recommended(LoE expert opinion).Additional lesions identified by MR that may modify the already planned surgical treatment should be ini-tially assessed with conventional imaging(re-evalua-tion of mammography and targeted US)and verified by imaging-guided biopsy(LoE II).In cases of suspi-ciousfindings solely detected by MRI,MR-guided biopsy localisation should be performed(LoE I). 2.4.StagingThere is no evidence to support routine staging for metastatic disease merely based on patient age.In young women with breast cancer,the recommended staging, including assessment of axillary nodal status,does not differ from that in all other older patients.3.Management of pre-invasive disease3.1.ChemopreventionThe panel agrees that chemoprevention treatments should preferably be administered within study protocols.3.2.Pre-invasive lesions(DCIS–DIN)Ductal Intraepithelial Neoplasia3.2.1.CounsellingCounselling in young women at increased risk for invasive recurrence or breast cancer should include fam-ily planning issues(fertility and contraception),even at diagnosis of a pre-invasive lesion.3360 F.Cardoso et al./European Journal of Cancer48(2012)3355–33773.2.2.SurgeryThe panel agrees that the surgical treatment of young patients presenting with intraductal neoplasia should in general not differ from that in older patients.Neverthe-less,young age is a variable that independently increases the local recurrence rate.42Therefore,the lesion must be removed with adequate surgical margins of at least 2mm.Achievement of clear margins(at least2mm)is strongly recommended.For those women who do not want to undergo re-excision or mastectomy in cases of close proximity to or focal positivity of margins,infor-mation needs to be given concerning the increased risk of local recurrence.As there is lack of data regarding safety of skin-sparing mastectomy in young patients, careful preoperative evaluation must be performed in order to properly select patients suitable for skin-sparing mastectomy,especially with nipple-areola complex (NAC)preservation.In such patients,evaluation of the retro-areolar margin,both intra-operatively by fro-zen section and post-operatively,is recommended. There is NO evidence for the necessity to perform pro-phylactic contralateral surgery in young women with unilateral DCIS or LIN(lobular in situ neoplasia)unless they are BRCA positive.As in older patients,sentinel lymph node biopsy (SLNB)is not routinely indicated in young patients with intraductal neoplasia.Nevertheless,it should be consid-ered whenever there is a substantial risk of underesti-mating the real disease extent by the pre-operative diagnosis(for example,a large cluster of microcalcifica-tions or extensive multifocal lesions)in order to avoid the risk of a second operation in the event that invasive disease is diagnosed at thefinal histology.The panel agrees that SLNB is strongly recommended in all patients undergoing mastectomy.3.2.3.RadiotherapyThe radiotherapy trial evidence is supported by retro-spective subgroup analyses according to age in large prospective trials.There is NO role for post-mastectomy radiation therapy in cases of DCIS with clear margins. However,it should be noted that older evidence refers to mastectomy that almost invariably included excision of the NAC.There is NO current evidence regarding preservation of the NAC,particularly not for young women with their known high-risk of recurrence.For this reason,data are urgently needed and this topic thus constitutes a RESEARCH PRIORITY.The current lack of evidence means that the issue of post-mastectomy radiotherapy after preservation of the NAC requires a full discussion and decision by the mul-tidisciplinary team with psychosocial issues considered.After breast conserving surgery,whole breast radio-therapy(WBR)should be given(LoE I).An additional radiation dose to the tumour bed(boost)should be con-sidered or entry into an appropriate prospective clinical boost trial43(LoE II).There is NO evidence to support withholding radiotherapy after breast conserving ther-apy for DCIS in young women.It should be noted,how-ever,that all studies addressing this point predominantly looked at older women.Partial breast irradiation(PBI), such as intra-operative radiotherapy(IORT)or other techniques,is not recommended as there are no data for DCIS.All randomised data on PBI so far refer to invasive cancers.4.Surgery4.1.Breast surgeryYoung age is an independent risk factor for increased local recurrence after breast conserving surgery and radiotherapy without affecting overall survival.44,45 Some of the histopathological characteristics such as lar-ger size,higher grade,presence of peripheral extensive intraductal component,vascular embolies and lymphoid stroma have been related to a higher risk of local recur-rence.Nevertheless,the panel agrees that surgical treat-ment of young patients presenting with invasive cancer–while being tailored to the individual patient–should in general not differ from that of older patients.Breast-conserving surgery followed by radiotherapy offers the same survival benefits as modified radical mastectomy in women with stage I or II breast cancer46,47and should therefore be considered as thefirst option whenever suit-able This may be particularly relevant for young women with breast cancer.Modern breast conserving surgery is aimed to remove the cancer while excising the smallest possible volume of tissue.Besides,and especially in young women,aesthetic outcomes and concept of female identity need to be taken into account.Skin-sparing and nipple-sparing mastectomy techniques seem to be ideal options both from an oncological and a cos-metic point of view.48Oncoplastic repair techniques should be offered to patients treated by breast conserv-ing surgery in order to maximise cosmetic results when-ever an obvious postoperative asymmetry can be estimated(LoE IC).Immediate breast reconstruction after mastectomy offers the same survival benefits as mastectomy without reconstruction(LoE IC).The options of immediate breast reconstruction should be discussed prior to surgery,ideally by a multidisciplinary team,in order to consider the issues related to possible indications for post-mastectomy radiotherapy.In young women with the diagnosis of either invasive disease or pre-invasive lesions,who are not BRCA mutation carriers,there is no evidence for improved overall survival by performing risk-reducing bilateral mastectomy.The risk for contralateral disease in young women with a family history who are not BRCA carriers does not seem to be substantially increased.49Neverthe-less,if,after receiving proper and thorough information based on the available data and on an appreciation ofF.Cardoso et al./European Journal of Cancer48(2012)3355–33773361。

优劣解距离综合评价法英文

优劣解距离综合评价法英文

优劣解距离综合评价法英文English:The Comprehensive Evaluation Method of Advantages and Disadvantages Resolution Distance, also known as the CODAS method, is a multi-criteria decision-making technique used to assess alternatives based on their performance across multiple criteria. This method involves several steps, including the determination of criteria, the normalization of criteria weights, the establishment of a decision matrix, the calculation of the performance scores for each alternative, and the final ranking of alternatives. One of the key features of the CODAS method is its ability to handle both qualitative and quantitative criteria, allowing decision-makers to incorporate a diverse range of factors into the evaluation process. Additionally, the CODAS method provides a systematic framework for resolving trade-offs between advantages and disadvantages, enabling decision-makers to make informed decisions that align with their objectives and preferences. By considering the relative importance of criteria and the performance of alternatives across those criteria, the CODAS method facilitates a comprehensive and transparent evaluation process that can support robust decision-making in various contexts.Translated content:综合评价法优劣解距离方法,也称为CODAS方法,是一种多准则决策技术,用于根据不同标准的绩效评估替代方案。

英语六级作文精准医疗

英语六级作文精准医疗

英语六级作文精准医疗Precision medicine, also known as personalized medicine, is an innovative approach to medical treatment and prevention that takes into account individual differences in people's genes, environments, and lifestyles. This approach allows doctors and researchers to predict more accurately which treatment and prevention strategies for a particular disease will work in which groups of people. It is a rapidly evolving field in healthcare that holds great promise for improving the way we prevent, diagnose, and treat diseases.One of the key elements of precision medicine is the use of genetic testing to identify a person's unique genetic makeup and understand how their body responds to medications. By understanding an individual's genetic predispositions, doctors can prescribe the most effective and personalized treatment options, minimizing the risk of adverse drug reactions and increasing the likelihood of successful outcomes. This level of personalized care has the potential to revolutionize the way we approachhealthcare and has the ability to significantly improve patient outcomes.In addition to personalized treatment plans, precision medicine also focuses on disease prevention. By understanding the genetic and environmental factors that contribute to the development of certain diseases, doctors can work with patients to develop personalized prevention strategies. This may include lifestyle changes, such as diet and exercise, as well as targeted screening and monitoring to catch diseases in their earliest stages.Furthermore, precision medicine has the potential to revolutionize the field of cancer treatment. By analyzing the genetic makeup of a tumor, doctors can identify specific mutations that are driving the growth of the cancer. This allows for the development of targeted therapies that attack the specific genetic abnormalities present in the tumor, leading to more effective and less toxic treatments.The benefits of precision medicine are clear, but there are also challenges that need to be addressed. One of the biggest challenges is the cost of genetic testing andpersonalized treatments. As technology advances and becomes more accessible, the hope is that the cost of theseservices will decrease, allowing more people to benefitfrom precision medicine.Another challenge is the need for more education and training for healthcare professionals. As precisionmedicine becomes more integrated into healthcare systems, doctors and nurses will need to be equipped with the knowledge and skills to interpret genetic data and develop personalized treatment plans.In conclusion, precision medicine has the potential to transform the way we approach healthcare, offering personalized treatment and prevention strategies that are tailored to an individual's unique genetic makeup. While there are challenges that need to be addressed, the promise of precision medicine is undeniable, and it has thepotential to revolutionize the field of medicine in the years to come.精准医疗,又称个性化医疗,是一种创新的医疗治疗和预防方法,它考虑了人们基因、环境和生活方式等个体差异。

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ORIGINAL ARTICLEEvaluation of Infant Accommodation UsingRetinoscopy and PhotoretinoscopyGina Marangoni Gabriel*and Donald O.Mutti †ABSTRACTPurpose.To compare PlusOptix PowerRefractor (PR)and Monocular Estimation Method (MEM)for measurement of infant accommodation and to assess the usefulness of applying individual calibration factors to PR data.Methods.Subjects were 41infants aged 3to 12months.Accommodative response was measured by MEM and PR at 33and 57cm,acuity by Teller Acuity Cards,and cycloplegic refractive error (RE)(tropicamide 1%)by retinoscopy (Wet Ret)and PR (PR C).Monocular wear of a ϩ2.00diopter (D)and ϩ4.00D lens established a PR calibration factor for each subject.Results.The median individual calibration slope was significantly different from 1.0(ϩ0.91;Wilcoxon signed-rank test:p ϭ0.03),yet there was no correlation between individual calibration slopes and the difference in RE by Wet Ret and PR C (r s ϭ0.05,p ϭ0.76).For 19infants with an accommodative response slope by PR of Ͼ0.50,the mean lag was not significantly different between methods (0.50D PR,0.48D MEM;p ϭ0.92;95%LoA ϭϮ1.78D).Despite the improvement in acuity with age (r p ϭϪ0.56,p Ͻ0.0001),neither age nor acuity had a significant effect on accommodative g was greater at 57cm (0.69D)than 33cm (0.30D,F 1,18ϭ6.3,p ϭ0.022),but lag was unrelated to RE (F 1,17ϭ3.3,p ϭ0.09).Accommodative response slopes for boys were larger (1.5)than for girls (1.0;F 1,17ϭ9.5,p ϭ0.007).Conclusion.MEM and PR provided similar estimates of RE and of accommodative lag once the PR data were screened for inattention using an accommodative response slope criterion.Adult-like accommodative responses between 3and 12months of age suggest that acuity at these ages is not limited by accommodative immaturity.Further,mature accommo-dation may attenuate RE-related defocus signals for emmetropization.(Optom Vis Sci 2009;86:208–215)Key Words:infant,accommodation,photorefraction,hyperopia,acuity,gender,development Assessment of the accuracy of the accommodative response may become an increasingly important part of the exami-nation of infants.Hyperopic defocus from accommoda-tive errors at distance,and particularly at the near distances that predominate in infancy,is reported to be a signal for emmetropiza-tion.1,2Experimental models using animals suggest that the coor-dinated growth of ocular components,with a goal of an ideal refractive state,is regulated by defocus on the retina.3–5Em-metropization is effective in decreasing the initial levels of hyper-opia in the majority of infants.The average cycloplegic spherical equivalent (SEQ)refractive error (RE)of human infants has been found to be about ϩ2.00diopter (D)at 3months,decreasing to ϩ1.00to ϩ1.50D at 12months of age with significant decreasesin hyperopia and its standard deviation with age during em-metropization.6,7It has been suggested that the operating range for human emmetropization extends from approximately ϩ1D to ϩ5D of hyperopia at 3months of age.7Failure to emmetropize affects approximately 7to 9%of the most highly hyperopic infants at the upper limits of this range.8,9Measurement of the accuracy of ac-commodation in these highly hyperopic infants may provide in-formation about the magnitude of defocus cues available to the infant and the likelihood for eventual emmetropization.It has also been suggested that the amount of accommodative lag may have diagnostic value in an older hyperopic infant or child once the period for emmetropization is past.10Rather than de-pending on the absolute level of cycloplegic RE,widely ranging clinical guidelines,11,12or unreliable subjective symptoms when deciding whether to prescribe a refractive correction,the clinician might use objectively measured accommodative lag as an indica-tion of whether the underlying hyperopia warrants correction.*OD,MS †OD,PhD,FAAOBoulder,Colorado (GMG),and The Ohio State University College of Optom-etry,Columbus,Ohio (DOM).1040-5488/09/8603-0208/0VOL.86,NO.3,PP.208–215OPTOMETRY AND VISION SCIENCECopyright ©2009American Academy of OptometryAccommodative error can be measured using several methods, including Monocular Estimation Method(MEM),Nott retinos-copy,and photoretinoscopy.Photoretinoscopy is often used to measure distance RE,13but can also be used to measure accommo-dative response or error.The PowerRefractor(PR)(PlusOptix, Germany,www.plusoptix.de)is a commercially available photore-fractor.The working range of REs for which the PR can accurately record is aboutϩ4.00D toϪ6.00D with respect to infinity.14–17 Although techniques for measuring accommodative error have been compared in young adult subjects,18,19infants’accommoda-tive error has only been studied by either dynamic retinoscopy20–23 or photorefraction.13,23,24A recent study of the validity of mea-surement of non-cycloplegic RE in infants using the PR found the technique to be valid,but suggested that individual calibration may be necessary to obtain accurate readings.They hypothesized that the readings might be influenced by optical characteristics of the eye,such as retinal reflectance,requiring correction by individ-ual calibration for each subject.25The PR might be preferred in a screening setting over MEM because of the lower cost associated with not having to use profes-sionally qualified examiners.Clinicians might consider using the PR rather than MEM because of the ability to examine the two eyes at once without the use of trial lenses at a close distance or the bright light of the retinoscope,thereby improving efficiency and comfort.The previous version of photorefractor,marketed by Multichannel systems,has been used effectively in the laboratory to study the accommodation of human infants.However,the sub-ject is examined using a beam splitter system to keep the PR, infant,and the fixation target coaxial.The data are scrubbed to eliminate fixations beyond15°,sections where data are missing, infants who do not respond to changes in target distance,and accommodative data where lag exceeds1D.26The currently avail-able PlusOptix version of the PR does not allow for all data to be extracted for scrubbing.Although the requirement that babies ac-commodate within1D of the target vergence allows for important analyses of accommodation to be performed,it may be of interest to determine the range of accommodative responses displayed by infants without imposed,strict limits.Additionally,the laboratory beam splitter arrangement may not be suited for general clinical use.The purpose of the current study was to evaluate the perfor-mance of the PlusOptix PR for the measurement of infant accom-modation in a general clinical setting against an accepted“gold standard”retinoscopic technique,MEM.The effect of individual calibration using slope,or slope and intercept,calculated from regression data after application of monocular trial lenses was also assessed.Age,acuity[Teller Acuity Cards,(TAC)],and cycloplegic RE were also analyzed for their role as covariates that might affect accommodation or instrument performance.METHODSForty-one infants aged94to366days were seen for this cross-sectional study between January2005and January2006.The mean age of the41infants in the study was7.68Ϯ3.08months with each month of age represented by at least two infants,except for8to9months(Fig.1).This research followed the tenets of the Declaration of Helsinki,was approved by the institutional review board at The Ohio State University,and informed consent was obtained from the parent or guardian of the subject after explana-tion of the nature and possible consequences of the study.To be included in the study,the infant must have been between3-and 12-months-old with a birth weight of at least5.5pounds(2500 grams),no history of ocular disease or active ocular inflammation, no strabismus or history of sensitivity to anesthetics or preserva-tives in eye drops,no cardiac,liver,or respiratory abnormalities, and must have been under the care of a pediatrician.Acuity MeasurementAfter informed consent,the infant’s binocular visual acuity was determined using preferential looking and TAC.The subject was seated on a parent’s lap,55cm from the cards and a stage.The parents were instructed not to move or give the infant any other cues about the location of the stripes.The examiner began by holding up the0.31cycles/degree stripes.The examiner judged the location of the child’s fixation by viewing through a peephole in the middle of the card.Successively smaller patterns were pre-sented until the subject no longer displayed preferential looking to the correct side of the card.When a correct look was no longer noted,that card was presented one more time.If the infant again showed no preference or a preference to the incorrect side,no more cards were shown.If a correct response was then noted two times, a card with smaller stripes was then presented.Final results were recorded as the cycles/degree of the last card with which a response was noted.Acuity scores converted to logMAR values for analysis. MEM Accommodation Measurement Accommodative error was then tested using MEM and PR at33 and57cm(MEM33;MEM57;PR33;PR57).During both techniques the room illumination was30lux and kept constant for each subject,who was seated on the parent’s lap facing the exam-iner.During MEM,a9ϫ9cm two-dimensional detailed picture of a cartoon mouse,as seen in Fig.2,was attached to a Keeler streak retinoscope.The size of the mouse target also allowed the infant to view part of the examiner’s face.The horizontal meridian of the right eye was neutralized only when the infant was attentive.At-tention was assumed when fixation,facial recognition,andpupil FIGURE1.Number of infants in each age group in months(days/31).Infant Accommodation by Retinoscopy and Photoretinoscopy—Gabriel and Mutti209constriction occurred.During an alert period,a lens from a lens bar was inserted briefly in front of the infant’s right eye.The lenses were arranged in intervals of0.50D,and the range of lenses that allowed for neutrality of the retinoscopic reflex was recorded.This technique was first performed33cm from the subject,then with the same mouse target at57cm.The order of PR and MEM was randomized,but within each technique the33cm measurement was done before the57cm measurement. PowerRefractor Accommodation Measurement During the binocular PR accommodative error measurement, the camera was placed at a constant distance of1meter from the infant’s eyes.Before the measurements began,the degree of fixa-tion error around the camera during which the PR would take measurements was changed to30°from the default setting of20°. This was done to allow for measurements to occur with the subject in up-gaze as he or she looked at the target.The targets used during PR measurements were multicolored plush toys held33cm (mouse)then57cm(firefly)from the infant’s eyes and just above the axis of the camera.These toys were selected for having broad-band spatial frequency content similar to those used in other infant accommodation work.26The PR measurements taken33and57 cm from the infant were converted to accommodative error first by finding the error in the horizontal meridian,then by adjustment for the dioptric demand at33cm and57cm with the following formulas:PR33accommodative error(D)ϭ3ϩPR33(horizontal) PR57accommodative error(D)ϭ1.754ϩPR57(horizontal) It should be noted that because infant RE was not corrected during measurement,accommodative demand was not a constant for all infants.PR Individual Calibration with MonocularTrial LensesCalibration information for the PR was obtained following the accommodative measurements.Aϩ2.00D loose lens was held in the right hand of the parent and was placed in front of the subject’s right eye.It was held as close to the infant’s right eye as possible without contact with the subject’s face during the measurement. Another plush toy(chicken)was held just above the camera.A similar measurement was then taken with aϩ4.00D lens and again with no lens.Individual calibration slopes were determined for each subject.The difference between the SEQ found in each eye using non-cycloplegic PR readings(PR1m)with no lens in place was subtracted from the difference between the SEQ found in each eye with aϩ2.00D and aϩ4.00D lens in front of the right eye.The change in anisometropia represented the effect of the monocularϩ2.00D orϩ4.00D lens.The calibration slope for each subject was calculated by linear regression using three points: the initial anisometropia with no trial lenses set to zero,and the increase in anisometropia relative to when no lens was in place as a function ofϩ2.00D,andϩ4.00D trial lenses.An example is shown in Table1.Cycloplegic REOne drop of0.5%proparacaine was put in each of the subject’s eyes followed immediately by2drops of1%tropicamide instilled 5minutes apart.Thirty minutes after the installation of the last drop,retinoscopy and PR were conducted in random order to measure cycloplegic RE in both eyes.During the retinoscopic mea-surement,the examiner found neutrality in two meridians using lens bars containing lenses at0.50D intervals.During each PR measurement for accommodative error,RE,and for calibration, the“Full refraction mode”was used and the target was wiggled to keep the subject’s attention.If needed,the examiner placed her head next to the toy to keep the infant interested at that distance until the PR stopped automatically with the“Autoshot”mode. This mode was chosen because the manufacturer’s software mod-ification for extracting data from the“Dynamic-mode”was not available to the investigators at the time of the study or to clinicians purchasing the unit.Once supplied,the software did not deliver continuous data;there were substantial random gaps in the record-ings.27These“Autoshot”data are intended to parallel what might be obtained in clinical use of the commercially available instru-TABLE1.Example calibrationdatafrom each of the three levels of anisometropia to yield the data used in the calibration regression(y axis)against0.00,2.00,and 4.00(x axis).The calibration equation for this subject was yϭ0.84xϩ0.19.FIGURE2.Cartoon mouse target attached to the retinoscope during MEM(not actualsize).210Infant Accommodation by Retinoscopy and Photoretinoscopy—Gabriel and Muttiment.During all PR measurements,the results of the PR were covered and masked from the examiner’s view.If the measure-ments did not automatically stop after about 30s,the examiner re-positioned the toy to allow the measurements to resume.For simplicity,only data from the right eye were used in PR accom-modation analyses.Statistical Methodsp values reported are from paired Student’s t-test unless noted otherwise.Correlation coefficients are Pearson when designated r p (equal variance assumptions met)and Spearman when designated r s (equal variance assumptions not met).F-statistics are from re-peated measures ANOVAs performed with test method and test distance as repeated factors,age,acuity,gender,and RE as between-subject factors.Statistical analyses were carried out using SPSS (v.15.0;SPSS,Chicago).RESULTS CalibrationRefractive error obtained with cycloplegic PR and cycloplegic retinoscopy (Wet Ret)is summarized in Table 2.The following analyses comparing distance RE by Wet Ret and PR C exclude one outlying subject with a 3.50D discrepancy between the two tech-niques.The SEQ for PR C was significantly more hyperopic com-pared with Wet Ret in each eye (OD mean difference ϭ0.40Ϯ0.77D,p ϭ0.002;OS mean difference ϭ0.62Ϯ0.93D,p Ͻ0.0001).The horizontal/vertical component of astigmatism (J 0)was more positive by retinoscopy than by the PR in each eye (OD mean difference ϭϪ0.16Ϯ0.30D,p ϭ0.001;OS mean differ-ence ϭϪ0.18Ϯ0.41D,p ϭ0.011).The oblique component of astigmatism (J 45)was statistically significantly more positive by retinoscopy than by the PR in the right eye only,but clinically negligible in amount (OD mean difference ϭ0.08Ϯ0.23D,p ϭ0.027).The comparability of Wet Ret and PR C data was also evaluated using orthogonal regression.The slope between PR C SEQ and Wet Ret SEQ was 1.05,which was not was significantly different from 1.0(95%Confidence Interval ϭ0.82,1.34,Fig.3).This indicates that despite the small hyperopic bias in PR,each tech-nique measured similar between-subject differences in RE.The width of the confidence interval for the slope indicates substantial individual variability.The 95%limits of agreement between PR C and Wet Ret were Ϯ1.50D [Fig.4(a)].Differences between PR C and Wet Ret were not correlated with the mean RE [r s ϭϪ0.002,p ϭ0.99OD;r s ϭϪ0.018,p ϭ0.91OS;Fig.4(a)].If this variability between the two techniques were due to sys-tematic errors,individual calibration should account in part for some of that variability.Individual calibration slopes were evalu-ated for their relationship with the individual differences between cycloplegic retinoscopy and PR measurements of distance RE.The median slope of calibration was ϩ0.91(25th percentile ϭ0.53,75th percentile ϭ1.10),which is significantly different from 1.0(Wilcoxon signed-rank test,p ϭ0.03).However,there was no correlation found between the difference in SEQ obtained by Wet Ret and PR C and the individual calibration slopes (r s ϭ0.05,p ϭ0.76).Nine subjects had calibration slopes that were Ͻ0.50.The median calibration slope when these subjects were excluded was ϩ1.02,which was not significantly different from 1.0(Wilcoxon signed-rank test,p ϭ0.94).There was still no correlation found between the difference in SEQ obtained by Wet Ret and PR C and the individual calibration slopes using only these 32subjects (r s ϭ0.095,p ϭ0.61).Adjustment of individual PR C values using the subject’s own calibration slope and intercept increased the 95%limits of agreement between PR C and Wet Ret in these 32subjects (Ϯ1.46D without adjustment and Ϯ2.12D with adjustment).Therefore,adjustment of RE measured with PR using individual cal-ibration slope,or slope and intercept,calculated by regression using data from monocular trial lenses did not improve the agreement with retinoscopy.This suggests that the primary source of variability be-tween the two techniques might be more random than systematic.AccommodationConsidering the results above,accommodation data were ana-lyzed without adjustment for the calibration results from trial lenses.PR data were adjusted for all subjects,however,bysubtract-FIGURE 3.Cycloplegic SEQ distance RE reading in the right eye (D)measured by PR C SEQ vs.retinoscopy (Wet Ret SEQ).The slope of 1.05was not was significantly different from 1.0but the 95%confidence interval was wide (95%CI ϭ0.82,1.34),indicating good but variable agreement.One subject with a 3.50D discrepancy between the two techniques has been removed.TABLE 2.Mean and SD for PR C reading ,and Wet Ret for the values of SEQ,J 0,and J 45in eacheyeInfant Accommodation by Retinoscopy and Photoretinoscopy—Gabriel and Mutti 211ing the 0.40D found in the right eye comparison with cycloplegic ing data from all infants,each of the four tech-niques showed a significant non-zero net average lag of accommo-dation (MEM 33ϩ0.37Ϯ1.05D,p ϭ0.03;MEM 57ϩ0.69Ϯ0.94D,p Ͻ0.001;PR 33ϩ1.30Ϯ1.45D,p Ͻ0.0001;PR 57ϩ0.44Ϯ1.05D,p ϭ0.011).PR at 33cm yielded a signifi-cantly larger lag than MEM at 33cm (difference ϭϩ0.97Ϯ1.57D,p Ͻ0.0001)and had the largest standard deviation of both distances and techniques (Ϯ1.45D).However,PR at 57cm was not significantly different from MEM at 57cm (difference ϭϪ0.21Ϯ1.23D,p ϭ0.28).The large accommodative error for PR at 33cm suggested that lack of attention may have affected readings at this closer distance.This factor was evaluated in two ways.First we scored the fixation patterns,the marks recorded on the screen of the PR of where the infant was fixating during the measurement,and excluded data where the infant fixated beyond 30°more often than within 30°during the measurement,if the infant’s fixation extended beyond more than two quadrants of the screen,if cylinder values were 1.0D more than found during PR C,or if fixation was more often central rather than on the toy held next to the PR.Undesirable patterns of fixation occurred 32%of the time at 57cm (13/41)and 71%of the time at 33cm (29/41).Poor fixation at one distance was not associated with poor fixation at the other distance (x 21ϭ0.35,p ϭ0.55).Elimination of data from infants displaying poor fixation did not significantly affect the higher lag found with PR at 33cm.Infants with good fixation had lag values of 1.11Ϯ1.61D with PR at 33cm and infants with poor fixation had lag values of 1.36Ϯ1.41D (independent sample t-test;p ϭ0.64).Because eliminating data from infants with poor fixation did not signifi-cantly decrease the lag found by the PR at 33cm,evaluation of the fixation pattern may not be a reliable indicator of attention.The second approach used a method suggested by Candy and Bharadwaj,which is based on the responsiveness of the infant to changes in target distance.26Infants were included in the analysis only if they displayed an accommodative response slope of Ն0.50.This criterion was met by 90%of infants during MEM 9(36/40)and by 46%of infants during PR (19/41,x 21ϭ17.7,p Ͻ0.0001).The two techniques provided similar assessments of accommodative response in this sub-sample of 19infants.The average slopes of the accommodative response function were not significantly different (1.30Ϯ0.54for MEM and 1.23Ϯ0.67for PR;p ϭ0.75).Repeated measures ANOVA of accommodative error using these 19subjects confirmed that the effect of instrument was not significant (F 1,18ϭ0.01,p ϭ0.92).The estimated mean accommodative error was 0.50D by PR and 0.48D by MEM [95%limits of agreement between methods ϭϮ1.78D;Fig.4(b)].Factors such as age,acuity,astigmatism,SEQ distance RE,test distance,and gender might affect estimates of accommodative er-ror.The mean visual acuity expressed as logMAR in the sample of n ϭ41was 0.88Ϯ0.82octaves,a value that improved signifi-cantly with age (Ϫ0.045logMAR per month,r p ϭϪ0.56,p Ͻ0.0001;Fig.5).The SEQ distance RE also decreased with age when measured with PR (Ϫ0.25D per month,r p ϭϪ0.61,p Ͻ0.0001)but not with Wet Ret (r p ϭϪ0.28,p ϭ0.077,Fig.6).The improvement in acuity was not due to changes in SEQdis-FIGURE 4.(a)Difference (PR C minus Wet Ret)vs.mean plots for cycloplegic distance RE.(b)Difference (PR minus MEM)vs.mean plots for accom-modative error.Data for 33cm and for 57cm are represented on the single plot.The shaded area represents the 95%limits of agreement.The horizontal line indicates the average difference betweenmethods.FIGURE 5.Age (days)vs.Visual Acuity (logMAR).Also included is the Pearson correlation coefficient r p and p-value.212Infant Accommodation by Retinoscopy and Photoretinoscopy—Gabriel and Muttitance RE,however.When visual acuity was modeled as a function of age and SEQ distance RE,the only significant factor was age (F 1,39ϭ17.5,p Ͻ0.0001).Despite these improvements in acuity with age,neither age (F 1,17ϭ0.87,p ϭ0.36)nor acuity (F 1,17ϭ0.00,p ϭ0.98)had a significant effect on accommodative error in a repeated measured ANOVA using the sub-sample of 19subjects.Astigmatism had no significant effect on the amount of accommo-dative error whether the astigmatism was measured using PR (F 1,17ϭ1.34,p ϭ0.26)or Wet Ret (F 1,17ϭ1.70,p ϭ0.21).There was also no significant effect of SEQ distance RE on accom-modative error (F 1,17ϭ3.3,p ϭ0.09).Accommodative error did depend significantly on test distance and g was greater at 57cm (0.69D)than at 33cm (0.30D,F 1,18ϭ6.3,p ϭ0.022).This finding was consistent with the average accommodative response slopes exceeding 1.0.This find-ing was also consistent across methods as there was no significant method by distance interaction (F 1,18ϭ0.003,p ϭ0.96).There was a significant interaction between gender and test distance (F 1,17ϭ5.2,p ϭ0.036,Table 3).The highest amount of lagoccurred in boys at 57cm (Table 3).The average accommodative response function slope for boys (22/41subjects)was therefore larger at 1.5than for girls (19/41subjects)at 1.0(F 1,17ϭ9.5,p ϭ0.007).DISCUSSIONValidity and CalibrationWhen data from all infants were analyzed,the accommodative error using PR at 33cm (1.30D)was substantially larger than at 57cm and larger than lag measured using MEM at either distance.The different amounts of accommodative error found when using MEM and PR at 33cm suggested that attention might be an important factor with PR.However,the MEM values in this study were very close to those found using Nott in previous infant studies by Banks and Brookman.21,22The range of neutral MEM values,high neutral vs.low neutral,was assessed within 0.50steps,but no range was detected in any infant at either distance suggesting that infants were not using relative accommodation when lenses were introduced in front of the eye,a common criticism of MEM.The average slope of the accommodative response function with MEM was also closer to values seen in previous studies and similar to that from PR once data were limited to subjects who were responsive to changes in target distance.13,20,21,23,24,28,29MEM appears to be a valid technique to measure accommodative error in infants 3to 12months of age.The PR appears to provide a valid measurement of RE,but with a small hyperopic bias.The SEQ distance RE found with PR C was between 0.40and 0.62D more hyperopic than that found with Wet Ret.The regression slope between the two methods measures of distance RE was not significantly different than 1.0.This agrees with several reports on the validity of PR measurements.15–17,27,30It has been suggested that calibration be done on individual sub-jects when measuring RE or accommodation with the PR,adjust-ing individual PR readings by a calibration equation obtained using trial lenses.The median infant calibration slope of 0.91found in this study is similar to the mean adult slope reported in recent literature.25These individual calibration slopes were not related to the differences in SEQ found between PR C and Wet Ret.The absence of a relationship between calibration slope and error and the increase in the limits of agreement after using both calibration slope and intercept suggests that adjusting PR C by these calibration data would not bring PR C any closer to the Wet Ret value.Correcting PR readings to create agreement with Wet Ret seems to only require adjustment by a constant,on the order of 0.50D found in this study.It is possible,however,that thisoffsetFIGURE 6.Age (days)vs.cycloplegic SEQ RE reading in the right eye (D)measured by (a)PR C SEQ;(b)retinoscopy (Wet Ret SEQ).Also included are Pearson correlation coefficients r p and p-values.TABLE 3.Estimates of the mean accommodative error by gender and test distance,adjusted for measurement method and distance refractiveerrorInfant Accommodation by Retinoscopy and Photoretinoscopy—Gabriel and Mutti 213between techniques may be different for each individual subjectrather than a constant for all subjects.Evidence for the appropri-ateness of using an individual adjustment value would come fromdata not gathered in this current study showing that individualvariations from the suggested group value of0.50D were repeat-able.Some evidence for this possibility can be seen in the highdegree of correlation between eyes for the difference between PR Cand Wet Ret(r pϭ0.69,pϽ0.0001).An additional limitation of these data is that most of the subjects in this study were of Euro-pean ancestry.The effect of retinal pigmentation on PR readingsalso needs further detailed study.Disagreement between the two methods’assessment of accom-modation might be better explained by differences in attentionrather than validity.Inattention was not reliably detected throughanalysis of the fixation patterns provided by the PlusOptix PRscreen.Accommodative error was still not comparable between thetwo techniques when data were separated according to the exam-iners judgment of the quality of fixation.This could be due to anincorrect choice of criteria about the quality of fixation.Alterna-tively,the PR might be using data for its eventual report of RE thatwere different from the points that provided the screen pattern.Screening the data by performance seemed a more effective met-hod.26Requiring that accommodative response slopes beՆ0.50created agreement between the average values provided by the twomethods with95%limits of agreement between methods ofϮ1.78D.Screening data by performance may still falsely eliminate somesubjects who show poor accommodative performance for reasonsother than poor attention.MEM does seem to command attentionbetter than PR with90%of MEM data being acceptable comparedto only46%of PR data.PR still has several potential advantages:measurement of the two eyes at once,no need for bright lightsmeaning better subject comfort,and the possible use of lay person-nel as examiners.Consistent with a recent recommendation,it maybe necessary to restrict the gaze allowance of the PR to15°or less sothat measurements will only be taken when the infant is looking inthe direction of,and hopefully attending to,the target.25To fit thetarget within this range without blocking the camera,mirrors maybe needed between the subject and the PR.Covariates and Accommodative ErrorThere was no correlation between the amounts of accommoda-tive error,as measured by either technique,with age.Previousstudies have shown that infant accommodation displays immatu-rities in terms of variability in the accommodative response slopeand the amount of focus errors.Both of these immaturities tend toimprove up to the age of3to4month,either reaching an adultlevel of performance,20or still showing occasional immaturity at3month.21,23Braddick et al.observed consistent focus behavioremerging between3and6month of age in response to a lowaccommodative demand of1.3D(75cm).13Infants presentedwith greater accommodative demands generally showed improve-ment in the accommodative response slope with age,but not toadult levels even by the age of5month.28,29Howland et al.ob-served values for the accommodative response slope in infants ofabout0.6with no change with age between2and7month.24Thecurrent study found that infants have adult-like and stable accom-modation by the age of3months once inattention during the use of the PR was removed as a large source of variability.This finding has interesting implications for the mechanism driving the accommodative response.Most researchers subscribe to the“sensory hypothesis”of accommodative development which proposes that throughout infancy,improving visual acuity allows a better stimulus for accommodation,which in turn makes for a more accurate accommodative response.But,in this study,accom-modative error did not change between3and12month of age, suggesting that accommodation is fully developed by3months. However,visual acuity improved between3and12month.This trend was similar to previous studies using TAC.31,32These results raise the question of how can accommodation be fully developed at 3months if visual acuity is still improving until12months?If the sensory hypothesis is correct,then lag should have been correlated with visual acuity changes over a similar time course.One possible explanation is that the TAC technique could have underestimated visual acuity.Any visual acuity changes measured from3to12 months may be the result of infants developing the skills necessary to perform the difficult preferential looking task rather than an actual improvement in visual acuity.This is supported by data showing that TACs measured a poorer visual acuity than VEP.33 Another possibility is that measurement error for accommodation might hide subtle improvements with age.However,it seems un-likely that average acuity could improve by a factor of nearly three times due to improvements in accommodation without measure-able changes in accommodative performance.The results for test distance,gender,and SEQ distance RE showed some important and clinically relevant patterns.In gen-eral,accommodative error was greater by0.39D at the further test distance of57cm.This is contrary to previous literature which has found increased lag with increased accommodative demand.20–22,24In-fants may have shown a more accurate response at the closer dis-tance due to proximal accommodation.It is also possible that it was easier for the infant to attend to the closer target because it was done before the57cm measurement each time.Whatever the source of the difference,boys seemed to show the effect more than girls.Girls’accommodative error was more uniform at each dis-tance whereas boys showed greater lag at57cm.This underscores the importance of testing at multiple distances,including infinity. In this dataset,near defocus was not significantly related to RE. Accommodative errors at either test distance appeared to carry no dose-related information regarding the underlying RE.Consider-ing recent information about the temporal integration of em-metropization signals,periods of exposure to minimal defocus at near that averages about0.50D may override longer exposures to signals for change in RE.34,35Understanding the signals for human emmetropization obviously requires more data.This study is lim-ited by being cross-sectional rather than longitudinal,by the small sample size,and by the limited range of REs.In summary,MEM and PR provided similar estimates of ac-commodative error once the data were screened for inattention using a performance-based criterion.Individual calibration using slope,or slope and intercept,calculated by regression from data after application of monocular trial lenses was not effective in improving measurement validity.Accommodation was adult-like by3months of age and did not vary by age despite improvement in acuity and decreases in hyperopic RE with age.Males showed214Infant Accommodation by Retinoscopy and Photoretinoscopy—Gabriel and Mutti。

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