Research ﬁndings from Most Research Findings Are False these corollaries consider each underpowered allergy forecast ashburn va buy deltasone uk, early-phase clinical factor separately allergy medicine ac buy 40 mg deltasone amex, but these factors often for Most Research Designs and for trials would be true about one in four inﬂuence each other allergy forecast dallas discount 10mg deltasone. Epidemiological studies of true effect sizes are perceived to allergy medicine zyxel purchase 40 mg deltasone with mastercard be exceeding 50% is quite difﬁcult to an exploratory nature perform even small may be more likely to perform get. Table 4 provides the results worse, especially when underpowered, large studies than investigators working of simulations using the formulas but even well-powered epidemiological in ﬁelds where true effect sizes are developed for the inﬂuence of power, studies may have only a one in perceived to be large. Or prejudice ratio of true to non-true relationships, ﬁve chance being true, if R = 1:10. A ﬁnding relationships exceed true ones 1,000prejudiced stakeholders may even from a well-conducted, adequately fold. May Often Be Simply Accurate sizes are in fact the most accurate Obtaining measures of the net bias Measures of the Prevailing Bias estimates of the net bias. It even follows in one ﬁeld may also be useful for As shown, the majority of modern that between null ﬁelds, the ﬁelds obtaining insight into what might be biomedical research is operating in that claim stronger effects (often with the range of bias operating in other areas with very low preand postaccompanying claims of medical or ﬁelds where similar analytical methods, study probability for true ﬁndings. History of science teaches us that scientiﬁc endeavor has often true relationships would not distort the Situation? Even if a Is it unavoidable that most research absolutely no yield of true scientiﬁc few relationships are true, the shape ﬁndings are false, or can we improve information, at least based on our of the distribution of the observed the situation? In such a null effects would still yield a clear measure it is impossible to know with 100% ﬁeld, one would ideally expect all of the biases involved in the ﬁeld. This certainty what the truth is in any observed effect sizes to vary by chance concept totally reverses the way we research question. The extent that observed ﬁndings investigators have viewed large However, there are several approaches deviate from what is expected by and highly signiﬁcant effects with to improve the post-study probability. Too large and too highly studies or low-bias meta-analyses, For example, let us suppose that signiﬁcant effects may actually be more may help, as it comes closer to the no nutrients or dietary patterns are likely to be signs of large bias in most unknown gold standard. They should large studies may still have biases the risk of developing a speciﬁc tumor. Moreover, large-scale literature has examined 60 nutrients wrong with their data, analyses, and evidence is impossible to obtain for all and claims all of them to be related to results. Statistical In some research designs, efforts Experiences from biases detected in principles for clinical trials. Lancet randomized trials: Comparison of protocols to understanding of the range of R 365: 488–492. I suspect several probability that a positive report is false: An extreme contradictory estimates may established classics will fail the test approach for molecular epidemiology studies. J Clin Epidemiol 58: Nevertheless, most new discoveries determinants in the new millennium. N Engl J Med 351: research teams has preceded a reported classiﬁcation of cancer: Class discovery 1250–1251. Clinical Research Methods for Surgeons Clinical Research Methods for Surgeons Edited by David F. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. The content and opinions expressed in this book are the sole work of the authors and editors, who have warranted due diligence in the creation and issuance of their work. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences arising from the information or opinions presented in this book and make no warranty, express or implied, with respect to its contents. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, since new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occur, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further, it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publishers, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. Cleary For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel: 973-256-1699; Fax: 973-256-8341; E-mail: humana@humanapr. The fee code for users of the Transactional Reporting Service is: [1-58829-326-2/06 $30. Unfortunately for surgery, his early exposure at Edinburgh to the brutality of operations in 1825 convinced him to reject his father’s plan for his career and pursue his interest in nature. His subsequent observations of how environmental pressures shaped the development of new species provided the essential mechanism to explain evolution and the disappearance of those species that failed to adapt. Today, surgeons face the same reality as new technology, progressive regulation by government and payers, medico-legal risks, and public demands for proof of performance force changes in behavior that our predecessors never imagined. We know that surgeons have always prided themselves on accurate documentation of their results, including their complications and deaths, but observational studies involving a single surgeon or institution have given way to demands for controlled interventional trials despite the inherent difficulty of studying surgical patients by randomized, blinded techniques. In a logical and comprehensive approach, the authors have assembled a group of experienced clinical scientists who can demonstrate the rich variety of techniques in epidemiology and statistics for reviewing existing publications, structuring a clinical study, and analyzing the resulting data. As these techniques become incorporated as standards into the curriculum of medical, public health, and nursing schools, the surgical professions must include them in their graduate training programs, professional meetings, and reporting practices. To ignore these new standards is to risk failing to continue to attract the best and brightest students into the field and becoming labeled as more technologically than scientifically advanced. Recent evidence suggests that even the most rigorously designed randomized clinical trial can be corrupted by biased reporting or data withheld on adverse events. The potential threat of industry control of such information must be a part of the training and review process as clinical research becomes more dependent on industry funding. Full disclosure of business relationships between industry and clinician-investigators has been a good start in defining ethical limitations, but it is essential that full disclosure include the registry of all clinical trials in a national database as recommended by the Consolidated Standards of Reporting Trials statement (Ann. These editors declared that its members would not publish the results of trials that had not been publicly registered, and most surgical journals have followed this lead. Currently there are several registries in existence and the World Health Organization is working on an online portal that would bind these databases into a single source. Darwin taught us that change in response to environmental pressures is essential to survival of the species, and leads not only to successful adaptation, but also to new vii viii Foreword directions for potential development. Surgeons have always been leaders in exploring new fields and this book will be a useful guide to better methods of clinical research. These analyses serve to identify potential areas for change in physician or patient behavior or in clinical processes. Implicit in the concept of clinical research is the notion that the findings will be used to modify clinical practice to achieve better outcomes. As such, clinical research has always been a necessary prerequisite for the advancement of surgery as a practice. In the past decade, basic science research in the surgical disciplines has advanced at a dizzying pace. Clinical research in surgery, however, has lagged far behind surgical basic science research. For example, the selected case series from a single academic center still remains one of the most common study designs employed by surgeons who address clinical research questions, despite the known limitations of this design. Although such clinical research techniques were appropriate 50 years ago—when the primary focus was on advances in surgical technique—they are inadequate for addressing the broader policy issues and clinical management questions faced by the surgeon today. The clinical research questions facing surgeons in the 21st century require sophisticated research techniques that most surgeons are, at best, only vaguely familiar with and, at worst, completely unfamiliar with. Evidence-based medicine is the foundation on which clinical research is built and is the explicit use of scientific data in decision making for clinical care. A requisite for evidence-based practice is the availability of high levels of evidence. Our colleagues in internal medicine have successfully adopted clinical research methods and have disseminated this information to trainees and practicing physicians through textbooks, educational series, and fellowship programs, such as the Robert Wood Johnson Clinical Scholars Program. Although it may be tempting to use existing resources to educate surgeons in clinical research methods, one must remember that diseases requiring surgical treatment are often unique, and that many of the methods used for looking at research questions in internal medicine are not easily applied to the surgical fields.
Box 4-1 summarizes several incidents that have added to allergy forecast manhattan ks discount 40mg deltasone overnight delivery concerns about bias in the reporting of industry-funded studies allergy medicine 10 months generic deltasone 10 mg fast delivery. Most involve an alleged failure to allergy medicine no juice purchase deltasone in united states online publish negative fndings from industry-sponsored clinical trials or long delays in publication allergy treatment naet discount generic deltasone uk. These incidents involved a number of pharmaceutical companies and different types of drugs. Sometimes the information became known only after legal proceedings led to the disclosure of confdential internal industry documents. In addition, systematic reviews that look at meta-analyses rather than individual clinical trials as the unit of analysis also fnd an association between industry funding and conclusions that favor the sponsor’s product. One study found that industry-supported reviews had more favorable conclusions, noted fewer reservations about the methodological limitations of the trials included, and were less transparent than reviews conducted by the Cochrane Collaboration. Another study, a review of meta-analyses of clinical trials of treatments for hypertension, found that meta-analyses conducted by individuals with fnancial ties to a single drug company were not more likely than meta-analyses conducted by individuals who received funding from other sources to have results that favored the sponsor’s drug. Financial ties to a single company were, however, associated with favorable conclusions by the authors of the meta-analyses. Among meta-analyses conducted by individuals with fnancial ties to one drug company, 27 of 49 (55 percent) reported favorable results from the meta-analysis, but 45 of 49 (92 percent) reported favorable 3 the Cochrane Collaboration describes itself as an independent, nonproft, international organization that develops and disseminates systematic reviews of health care interventions and promotes the creation and use of evidence to guide clinical and policy decisions (see. It relies primarily on volunteers who conduct reviews according to specifc standards. It has policies intended to limit bias and restrict fnancial conficts of interest in its activities. The outcomes at 6 months showed an advantage for the study drug, but the outcomes at 12 months showed no advantage compared with the use of the control drugs (Wright et al. Published clinical trials suggest that selective serotonin reuptake inhibitors have a favorable beneft-risk profle in children with depression. When unpublished data were considered, the evidence indicated that the risks appeared to outweigh the benefts for all but one drug in this class (Whittington et al. The results of trials of paroxetine that demonstrated an increased risk of teenage suicide or a lack of effcacy were not published. The data were revealed only after a lawsuit was brought against the manufacturer (Gibson, 2004). The manufacturer of aprotinin, an antifbrinolytic drug used in cardiac surgery to decrease bleeding, withheld data that use of the drug increased the risk of renal failure, heart attack, and congestive heart failure (Avorn, 2006). The results of a clinical trial that compared the use of ezetimibe plus a statin with the use of a statin alone in individuals with elevated cholesterol levels were not published until 2 years after the conclusion of the trial. The results showed no difference in carotid artery wall thickness in the two groups (Kastelein et al. The results of a pivotal clinical trial of a blood substitute (PolyHeme) in patients undergoing elective vascular surgery were not released for 5 years after the trial was stopped by the sponsor. The trial showed signifcant increases in the rates of mortality and heart attacks in the group receiving the experimental intervention (Burton, 2006; Northfeld Laboratories, 2006). The manufacturer of an implantable cardioverter-defbrillator allegedly failed to report critical, potentially fatal design defects for more than 3 years (Hauser and Maron, 2005). The manufacturer of a brand-name thyroid hormone attempted to block the publication of an article showing that a generic thyroid replacement therapy had bioavailability similar to that of the brand-name preparation (Rennie, 1997). The authors of the review suggested that there was a discordance between the data that underlie the results and the interpretation of these data in the conclusions (Yank et al. Thus, although there is little direct evidence that industry sponsorship has led to deliberate skewing of the results or reporting, there are multiple cases in which industry sponsors have withheld important study results and in which the conclusions presented in the reports appear to overstate the study fndings. The risk is particularly relevant in clinical trials, when the prospect of direct harm to patients (as well as research participants) is a more immediate concern than is the case for most nonclinical research. In this case, confict of interest policies may help prevent an erosion in public confdence beyond that which may result from research that documents bias or the withholding of data. Ghostwritten research articles also raise concerns about bias as well as the ethics of author attribution. A confict of interest is inherent in this practice when the industry sponsor has more control over the article than the nominal authors. Chapter 5 discusses ghostwriting and also participation on speakers bureaus and recommends that academic medical centers forbid faculty from accepting the authorship of ghostwritten articles and participation in speakers bureaus. Terms of Research Contracts Some academic health centers allow provisions in research contracts that give industry sponsors important control over the reporting of research fndings. In a 2004 survey involving academic medical centers, 7 percent of respondents reported that their institution would allow industry sponsors to revise manuscripts or decide whether results should be published, and more than 5 percent reported that they were unsure about the answers to both questions (Mello et al. Half allowed the sponsor to draft the manuscript, whereas only 40 percent prohibited that practice. Seventeen percent of the responding institutions reported disputes over control or access to the data from research. Funding arrangements with contract research organizations have also raised concerns about inappropriate control by industry sponsors (Bodenheimer, 2000; Mirowski and Van Horn, 2005; Shuchman, 2007; Lenzer, 2008). Although the committee found no systematic assessments or comparisons of bias in research conducted by these organizations, any lack of such controls over unilateral industry infuence raises concerns. Issues Involving Research Participants or Students As Chapter 3 discussed, academic medical centers vary in their policies on disclosure to research participants of investigator’s conficts of interest. It also noted that several surveys suggest that participants in clinical trials currently are not highly concerned about investigators’ fnancial conficts of interest. Most respondents report that their decision to enroll in a clinical trial would not be greatly affected by learning that the researcher had a fnancial relationship with the sponsor. Some respondents even believed that a greater fnancial interest would make the investigator do a better job (Weinfurt et al. It is not clear, however, whether participants in clinical trials understand how conficts of interest could potentially compromise study designs and the protection of research subjects or how they could contribute to bias in the reporting of the results—with the possible consequence being harm to future patients. Furthermore, it is not clear that it is reasonable to expect the average participant to understand these issues. In any case, even if research subjects are not worried about conficts of interest, other important members of the public may be concerned. As noted in earlier chapters, the political and economic support of the research enterprise depends critically on the confdence of the opinion leaders in government, the media, and academia. When they have doubts about the integrity of the enterprise, that essential support may begin to erode. Such exploitation is unethical and also has the potential to bias the design, conduct, and fndings of research. Areas that may raise problems with undue infuence include decisions about an individual’s inclusion or exclusion from a research project; the focus, design, and conduct of a study; the publication of research fndings (including the suppression of publication); and the treatment of intellectual property interests. This presumption can be rebutted when compelling circumstances justify the researchers’ involvement. In addition, only a minority of the medical schools with such a policy had defned the compelling circumstances that would support an exception. It also presented informative case studies and a template for analyzing these cases to illustrate how different situations can be evaluated for the existence of a confict of interest, the risks presented by the confict, the options for eliminating or managing a confict, and the compelling circumstances that might justify the participation of an investigator with a confict of interest in research with human participants. Among the examples of risks cited in the template is the extent to which the reputation of the researcher with a confict of interest or his or her institution could be damaged, even if a plan for managing the confict is created and implemented. One recommendation did, however, call for medical center confict of interest committees to review investigator conficts of interests in certain nonclinical studies. The committee found much less information and analysis about confict of interest policies affecting nonclinical biomedical research than about policies affecting clinical research. Universities and medical schools may have different policies for different kinds of research or may apply different criteria to evaluate conficts of interest in research that does not involve humans (as reported in Chapter 3). One university, however, recently adopted a confict of interest policy that explicitly states that [t]o protect against the risks that may accompany relationships with Interested Businesses, it is not ordinarily allowable for an Individual who has a Signifcant Financial Interest in an Interested Business to Conduct Research involving that Interested Business (Columbia University, 2009). Although an immediate risk to research participants does not exist in basic research, the potential for bias in basic research does exist. The result could be the initiation of clinical trials based on fawed basic science. In general, a weighing of risks against expected benefts should allow confict of interest committees to apply policies while taking into account differences in clinical and nonclinical research, including differences in what constitutes a reasonable justifcation for researchers to be involved in research in which they have a fnancial stake. The frst report provides a checklist of topics, including publication rights and intellectual property, to be covered in research contracts. Among other elements, one or both reports call for contracts to explicitly grant researchers free access to study data, to include no restrictions on publication (except for a slight delay for sponsor review and possible fling of a patent application), and to require a good faith and timely effort to publish the results of research in a peer-reviewed journal.
If surgery is scheduled for early morning allergy forecast key west discount generic deltasone canada, particle size as it is a macromolecule-targeting agent; it targets injection and imaging may be safely performed the afterdextran-mannose receptors on the surface of macrophages allergy forecast nyc mold buy deltasone 5 mg free shipping, noon prior to allergy ready cheap deltasone 10 mg line the surgery  allergy treatment chennai buy deltasone with amex. Dendritic cells efficiently present the mannose receptor-mediated uptake of Lymphoseek to T cell lymphocytes in lymph nodes . The investigated and suggested Sulphur colloid 350–5,000 (see text) 100–220 (filtered) activities vary considerably. When using superficial nanocolloid (Nanocis) (periareolar, subdermal, intradermal, or subareolar) injections, Tin colloid 800 30–250 large volumes of injectate may interfere with normal lymphatLabelled dextran 800 10–400 ic flow; therefore, volumes of 0. Hydroxyethyl starch 1,000 100–1,000 With peritumoral injections, larger volumes. Eur J Nucl Med Mol Imaging Radiolabelled colloid particles are suspended; thus, they the site of injection can be gently massaged after tracer may settle by gravity if left in a motionless syringe for more administration to improve drainage of the tracer. A syringe with colloid should be gently also be employed if passage of activity from the injection site rotated immediately prior to administration of the colloid to is delayed at any time during the study [61, 62]. Imaging procedure Injection procedure Quality control the optimal injection technique has been the subject of lively Quality control should be routinely performed on the imaging debate. One major advantage of superficial injections is that they Imaging protocol are easy to perform. A subdermal, periareolar, intradermal, or subareolar injection, however, is often more painful than a Imaging is recommended before any operation, as there is peritumoral injection. The addition of pH-balanced 1 % lidopatient variability in breast lymphatic drainage into the caine to the radiopharmaceutical often improves patient comaxilla and extra-axillary regions. The use means of determining if there is uptake of activity in any of peritumoral injections requires careful investigation of a node, and it improves the likelihood of identifying all patient’s prior imaging and medical records, particularly if the relevant node beds and thus the likelihood of locating all tumour is nonpalpable. The energy care should be exercised to avoid injection into the dead space window should be 15 % (±5 %) centred on the 140 keV 99m of a seroma resulting from a previous excisional biopsy or into photopeak of Tc. After almost 20 years of experience, it is generally accepted Patient positions Most commonly, at each acquisition time that both deep and superficial injection approaches are valid point at least two or three images are acquired: anterior, lateral, and that they are often complementary. Anterior images are acquired with both injection techniques (deep and superficial) may even the patient lying supine on the bed of the imaging system. It is recommended the patient extend her/his arm as breast lymphatics showed there are alternative lymphatic for the anterior images. The authors also the patient lying supine, with her/his arm on the side with found that separate lymphatic networks exist in the ventral cancer (R/L) extended. Rotation of the patient places tumours no matter in which quadrant of the breast they were the breast with cancer dependent toward the patient’s midline. This reduces attenuation of uptake in axillary nodes and Eur J Nucl Med Mol Imaging reduces the potential for projection overlap of the uptakes at registered with anatomical data. In this position, the patient’s involved breast is contrast and spatial resolution than planar images. In this case, if possible, the thus providing a valuable road-map for surgery . Acquisition paramePlanar (static) imaging ters should include a matrix size of 128×128 (4–5mm Planar (static) imaging should be performed 15– pixels) and 120 or 128 projections over 360° with 20– 30 min, 1 h, and 2–4 h after injection, and as needed 25 s/projection. At least two, preferably all three, lution recovery, the number of projections or the time per of the following images should be acquired: anterior, 45° projection may be reduced as recommended by the venanterior oblique, and lateral. All images obtained should be stored in a permanent Transmission imaging form according to national and other relevant regulations. The patient’s body contour should be delineated for positioning and referencing foci of activity. Imaging from at least two projections should be Because the amount of tracer uptake in a node does not performed. Anatomical localization of tracer uptake is therefore more than one node is found in the same region, some sufficient. Eur J Nucl Med Mol Imaging Image processing should be performed after the patient is anaesthetized to avoid painful injection. If local anaesthesia is to be used, the local No particular processing procedures are needed for planar anaesthetic should be administered using a separate syringe images. A logarithmic scale to local anaesthetics in the same syringe results in immediate enhance low-count areas instead of a linear scale is preferable precipitation of 4–9 % drug complex. When drainIt is important to be aware of contraindications for the use age to more than one anatomical region is seen, each of of blue dyes. Blue dye can induce anaphylactic reactions that reorientations of the images acquired, the radiopharmaceutical, quire resuscitation in 0. Hypersensitivity the method of administration, the dose and volume of activity to the product is the only contraindication. Blue dye should also not be used if there is report should be available by the time the patient arrives in the prior evidence of a patient having had an allergic reaction to surgical suite—in electronic form or as hard copy. If this is not this type of agent or of a patient having severe renal impairpossible, the critical information should be relayed directly to ment [79–85]. A close working relationship between the imaging department and the surgeon are critical for accurate disseminaRadioguided surgery tion of information regarding numbers and locations of nodes. It is thus advisable that the major component with information obtained using blue dye injected during of collimation be in the form of a detachable collimator of surgery. This allows it to be removed when it is for decreasing false-negative findings and increasing sensitivnot required, rendering the probe more compact and more ity [45, 62]. The detector should be constructed to offer a Currently, the commonly used dyes are patent blue V, high level of shielding against radiation hitting the side of isosulfan blue, and methylene blue. The whole system should be designed around the primary tumour in a manner similar to that for and constructed to be suitable for intraoperative use . Care should be exercised to avoid easy manoeuvrability and constructed so as to be suitable injection into the dead space of a seroma . Eur J Nucl Med Mol Imaging When used intraoperatively, a probe is placed in a sterile visualized, increasing false-negative results. A display false-negative results, the open axilla should be palpated and capable of providing clear instantaneous and cumulative suspicious lymph nodes harvested, even if these are neither counts is a major requirement. Neither body, however, enforces mandatory also be a biohazard and should be handled accordingly. Thus, informaterials should be educated as to their safe handling mation regarding compatibility with regional requirements and disposal. Appropriate education of surgical suite should be separately sought from the manufacturer of a device. In working with the probe, it is important to direct the probe away from activity at the injection the majority of patients with preoperative lymphoscintigraphic sites. While logistically difficult in recorded with the probe pointing away from the injection site, most centres, a second radiotracer injection, at perhaps a difnodal activity, or other physiological accumulations. Due to the limited spatial resolution of detected preoperatively or intraoperatively and the status of gamma cameras, nodes closer than about 15–20 mm may the axillary nodes cannot be determined. Thus, after removal of one node, another tumour location other than the upper outer quadrant, and hot node may still be present. The number of nodes to remove from any one basin preoperative scintigraphic nonvisualization is not yet known. Eur J Nucl Med Mol Imaging Histopathology 112–115, 118, 119] have been reported by several investigators and are offered in relevant radiopharmaceutical package Before specimens are sent for histological examination, they inserts [120, 121]. Table 3 is a summary and interpretation of should be evaluated ex vivo using the probe to demonstrate much of the available data. This evaluation should be All of the published data indicate that exposures to patients performed on all nodal specimens and all tumour specimens. In patients who are breast feeding, nursing should sensitivity of the intraoperative diagnosis is variable and many be suspended for 24 h following radiopharmaceutical adminfacilities do not adopt it at all . The dose is very small relative to that received from studies in many centres; it is in routine use in others . One estimate of the dose from a transmission istered, are well below recommended limits for both public source is 0. The estimates are Evaluation of internal mammary and other extra-axillary dependent on various acquisition parameters. The total exponodes sure in such cases is the emission-generated dose plus the transmission-generated dose. Both types of cancer have high prevalence of the outcome of treatment and survival [140, 142]. Prior excisional biopsy Ductal carcinoma in situ Lymph drainage is probably changed in patients who have undergone breast surgery.