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The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol. The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

In this issue of the Journal, a study by Heijnsdijk et al.1 shows the way to a resolution of the long-standing controversy about screening for prostate cancer. This is welcome news, since the 2009 reports of the long-awaited European and North American randomized trials of prostate-specific antigen (PSA) screening did not settle the matter.2,3 In the American trial, screening did not reduce prostate-cancer mortality, but the results were confounded by frequent PSA screening in the control group (e.g., 52% in the sixth year).3 In the European Randomized Study of Screening for Prostate Cancer, the screening of men between the . . .

In October 2010, the National Cancer Institute (NCI) announced that patients who were randomly assigned to screening with low-dose computed tomography (CT) had fewer deaths from lung cancer than did patients randomly assigned to screening with chest radiography. The first report of the NCI-sponsored National Lung Screening Trial (NLST) in a peer-reviewed medical journal appears in this issue of the Journal.1 Eligible participants were between 55 and 74 years of age and had a history of heavy smoking. They were screened once a year for 3 years and were then followed for 3.5 additional years with no screening. At . . .

In response to a mail survey, 225 leading general internists provided their opinions of the relative importance to patients of thirty medical innovations. They also provided information about themselves and their practices. Their responses yielded a mean score and a variability score for each innovation. Mean scores were significantly higher for innovations in procedures than in medications and for innovations to treat cardiovascular disease than for those to treat other diseases. The rankings were similar across subgroups of respondents, but the evaluations of a few innovations were significantly related to physicians' age. The greatest variability in response was usually related to the physician's patient mix.

Stage A 48-year-old man who had received three cadaveric renal transplants had a 10-day history of painless edema of the legs. He was not short of breath at rest but had had moderate dyspnea on exertion for a week. Response The edema may be hydrostatic in origin, from either heart failure or other causes, or oncotic in origin, from hypoalbuminemia; bilateral deep venous thromboses would be unusual. The patient's shortness of breath may be caused by heart failure or fluid overload, but it could indicate lung infection. He is immunocompromised, so we need a broad differential diagnosis that includes opportunistic . . .

WITHIN THE SPACE OF SEVERAL MONTHS, 2 VERY large randomized trials of screening for lung cancer have reported their findings, which fortunately complement one another. The National Lung Screening Study (NLST) found that annual lowdose computed tomography (CT) reduced lung cancer mortality by 20% relative to annual chest radiography. In this issue of JAMA, investigators from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Randomized Trial report that annual screening chest radiography does not reduce lung cancer mortality relative to no screening. Should clinicians infer that screening with low-dose CT reduces lung cancer mortality by 20% relative to no screening? This editorial addresses that question and several other aspects of the PLCO trial. Why would the National Cancer Institute sponsor a large trial of screening for lung cancer with chest radiography? Although 6 randomized trials, most of them published in the 1980s, found no evidence that screening radiography reduced lung cancer mortality, the control group received screening chest radiography in all but the Mayo Lung Project. This study had important protocol deviations and was relatively small (9211 participants randomized; 366 cancers detected). So the body of evidence was inconclusive according to the investigators who designed the PLCO trial. The PLCO trial measured the effect of a package of screening interventions aimed at preventing death from 4 cancers. Patients were individually randomized to a usual care group or to an intervention group that was screened periodically for prostate, lung, colorectal, and ovarian cancer for 3 years and then monitored for PLCO cancers (a stop-screen design). Recruiting targeted the US general population aged 55 through 74 years. The study was designed to have a 90% probability of detecting a 10% reduction in lung cancer mortality. Over 8 years, 77 445 participants were randomized to screening and 77 456 to usual care. Half of the participants were ever-smokers; 10% were current smokers. Lung cancer mortality, the primary end point, was 14.0 per 10 000 person-years of follow-up in the intervention group and 14.2 in the control group (rate ratio, 0.99; 95% CI, 0.87 to 1.22). In high-risk patients who met the NLST eligibility criteria, the outcome was similar except for higher lung cancer mortality rates. The PLCO trial shows that a short-term chest radiography screening program has no effect on lung cancer mortality. The only potential concern about the validity of this conclusion is the reporting of follow-up contact with the trial participants. The authors’ diagram of the flow of participants through the trial (Figure 1) does not state the number of participants in the usual care group that the authors were unable to contact during follow-up. Differential ascertainment of lung cancer mortality and, especially, incidence could occur if follow-up rates were unequal in the screening and usual care groups for reasons linked to lung cancer incidence and mortality. Most of the 1696 cancers were interval cancers (n=198), arose in patients who were never screened (n=193), or arose in patients who had completed 3 rounds of screening (n=998). These far outnumbered the screen-detected cancers (n=307). The large number of deaths from cancers diagnosed after screening is a reminder of the transitory benefit from a short-term program of screening for lung cancer. The best test of lung cancer screening in high-risk individuals would be a trial of lifelong screening. With a stop-screen design, the true effect of screening is unclear because of uncertainty about how long to monitor patients after screening. At one extreme, stopping right after the last screen will miss cancers that screening did not detect but that would have been diagnosed if monitoring had been extended into the postscreening period. Stopping monitoring too soon, therefore, may overestimate the effect of screening by covering up some of its failures. At the other extreme, extending the period of monitoring long past the time when the last cancer missed by screening would have been diagnosed will underestimate the

The departing Editor draws some lessons from his tenure at Annals of Internal Medicine. The main lesson is that evaluating research requires intensive effort by editors and statisticians. Journals ...

The U.S. Congress asked the Institute of Medicine to elicit input from stakeholders on which research topics should have the highest priority for comparative effectiveness research (CER) funding an...

In 2005, the International Committee of Medical Journal Editors (ICMJE) initiated a policy requiring investigators to deposit information about trial design into an accepted clinical trials registry before the onset of patient enrollment.1 This policy aimed to ensure that information about the existence and design of clinically directive trials was publicly available, an ideal that leaders in evidence-based medicine have advocated for decades.2 The policy precipitated much angst among research investigators and sponsors, who feared that registration would be burdensome and would stifle competition. Yet, the response to this policy has been overwhelming. The ICMJE promised to reevaluate the policy . . .

Ignoring complementary and alternative medicine (CAM) is not an option. The widespread use of CAM by patients is a mandate to the scientific community to improve our relatively weak scientific unde...

Given the high stakes of surgical treatment, where should patients go when they need surgery? Common sense and a growing literature suggest that they should seek surgeons and hospitals that frequen...

As editors of general medical journals, we recognize that the publication of clinical-research findings in respected peer-reviewed journals is the ultimate basis for most treatment decisions. Public discourse about this published evidence of efficacy and safety rests on the assumption that clinical-trials data have been gathered and are presented in an objective and dispassionate manner. This discourse is vital to the scientific practice of medicine because it shapes treatment decisions made by physicians and drives public and private health care policy. We are concerned that the current intellectual environment in which some clinical research is conceived, study subjects are recruited, . . .

The Federated Council of Internal Medicine has developed a resource guide to help internal medicine residency programs produce internists who are prepared for today's practice of internal medicine and the challenges of practice in the future. The guide situates general internal medicine as the primary care profession that focuses on preventive, short-term, and long-term care of adult patients. It assumes that a single pathway is sufficient for educating general internists and subspecialty-bound trainees. It identifies the learning experiences that should be part of general internal medicine residency training, lists the clinical competencies that are important for primary care practice, and describes the role of the integrative disciplines that should inform the care of every patient. It also describes a process that program directors and local program committees can use to develop competency-based curricula.

We, the Editors and the Scientific Publishing Committee of the American Heart Association journals, support the principles enunciated in the editorial “Clinical Trial Registration: A Statement From the International Committee of Medical Journal Editors.” We look forward to working together in addressing the details of their implementation. Donald Heistad, MD, Editor-in-Chief, Arteriosclerosis, Thrombosis, and Vascular Biology Joseph Loscalzo, MD, PhD, Editor-in-Chief, Circulation Eduardo Marban, MD, PhD, Editor, Circulation Research John E. Hall, PhD, Editor-in-Chief, Hypertension Vladimir Hachinski, MD, Editor-in-Chief, Stroke Ivor J. Benjamin, MD, FAHA, Chair, American Heart Association Scientific Publishing Committee Altruism and trust lie at the heart of research on human subjects. Altruistic individuals volunteer for research because they trust that their participation will contribute to improved health for others and that researchers will minimize risks to participants. In return for the altruism and trust that make clinical research possible, the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsor’s product. Unfortunately, selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision-making. …

Sixteen months ago, comparative effectiveness research (CER) began its rapid rise, when the American Recovery and Reinvestment Act of 2009 allocated $1.1 billion for CER. This progress report summarizes how the recipients of the funds-the National Institutes of Health, Agency for Healthcare Research and Quality, and Office of the Secretary of the U.S. Department of Health and Human Services-are spending the $1.1 billion, how the Institute of Medicine priority topics have fared in the agencies' funding programs, and the developing plans for a national CER program. As the United States works to absorb 32 million currently uninsured people into the health care system while simultaneously improving the quality of care and slowing cost increases, CER will increasingly be a necessary component of this change.

The articles in this issue by Abernethy and colleagues, Gillick, and Tillman and associates shine a bright light on a weak point in our efforts to inform clinical practice by the best possible evid...

Pletcher and colleagues' cost-effectiveness analysis in this issue found that some statin strategies had acceptable economic value in preventing CHD. Wong and associates provide a brief introductio...

Science advances along an irregular path, as researchers attempt to replicate the work of others and build on knowledge. Reporting guidelines are important to this iterative process because they he...

This issue includes the current USPSTF guidelines on screening for colorectal cancer, an updated systematic review of key questions, and a decision analysis to compare testing strategies and decide...

A seeding trial is marketing in the guise of science. In 2003, Annals published a seeding trial sponsored by Merck & Co. No one told Annals the true purpose of the trial until the Editor received a...

This issue marks the marriage of 2 publications with large and loyal readerships—Annals of Internal Medicine and ACP Journal Club. Beginning today, ACP Journal Club will appear in the second of the...

In this issue, Laiyemo and colleagues use data from the Polyp Prevention Trial to assess the clinical utility of current clinical guidelines for using findings at index colonoscopy to decide when t...

This issue includes a policy paper from the American College of Physicians on effective health care systems in other countries and what the United States might learn from them. During 2008, Annals ...

To review the evidence on four questions about screening asymptomatic adults for arterial hypertension: Is hypertension a significant health problem? Is it detectable at an early, presymptomatic stage? Is treatment available and effective? Do the benefits of screening outweigh the costs and risks?We did a computerized search of the MEDLARS data base to identify community-based trials of drug therapy for mild hypertension; other relevant citations are included when appropriate.We approached the preliminary questions in our analysis by narrative review and argument. The estimates of therapeutic efficacy are based on previously published meta-analyses. The cost-effectiveness of screening was addressed by formal mathematical modeling of the effect of screening on various U.S. populations. RESULTS OF ANALYSIS: Hypertension is clearly a significant health problem. It can be detected early, and effective treatment is available. Screening asymptomatic adults for hypertension has benefits that compare favorably to the risks and costs involved. According to our estimates, screening is most cost-effective for older adults compared with younger adults and for men compared with women and is highly sensitive to the cost of therapy for mild hypertension.We recommend hypertension screening for all adults. We also discuss the frequency and setting of screening activities. When a low-cost therapy is used, the cost-effectiveness of screening for hypertension compares favorably with other cardiovascular interventions.

The medieval European craft guilds are the antecedents of today's professions. As a commentary on the article by Campbell and colleagues in this issue, the Editor argues that, like the guilds, the ...

Among more than 45 000 women randomly assigned to conventional or liquid-based cervical cytology, the frequency of false-negative results was the same for both methods, but liquid-based cytology ha...

In this issue, Halvorsen and colleagues remind us about framing effects. They report that the way in which an outcome is described strongly influences whether a patient will consent to an intervent...

A community of scientists arrives at the truth by independently verifying new observations. In this time-honored process, journals serve 2 principal functions: evaluative and editorial. In their evaluative function, they winnow out research that is unlikely to stand up to independent verification; this task is accomplished by peer review. In their editorial function, they try to ensure transparent (by which we mean clear, complete, and unambiguous) and objective descriptions of the research. Both the evaluative and editorial functions go largely unnoticed by the public--the former only draws public attention when a journal publishes fraudulent research. However, both play a critical role in the progress of science. This paper is about both functions. We describe the evaluative processes we use and announce a new policy to help the scientific community evaluate, and build upon, the research findings that we publish.

This issue of Annals contains the inaugural installment of a new section, “In the Clinic.” The goal of “In the Clinic” is to better connect Annals to clinical practice. This section focuses on a si...

As the health of the public improves, many more people are living into their ninth and tenth decades. Should these people undergo screening tests? If not, at what age do the costs and harms of screening outweigh its benefits? Few studies of preventive medicine interventions have enrolled patients past the age of 75. Closing this gap in our understanding of disease prevention should be high on the list of national health research priorities. For the present, however, each patient will require an individualized decision. What rules of thumb should we use to help older patients decide when we should stop screening them for high cholesterol levels, cancer, and other diseases? From the individual patient's perspective, the most useful heuristic is to compare the harms and benefits of screening for that patient. Most of the benefit in screening for a disease is reduced disease-specific mortality, and this benefit happens to people who would have died of the disease except for the interventions triggered by a positive screening test. Harm can happen to anyone, including people who never develop the disease. Because benefits increase as the risk of disease increases, the balance of harms and benefits will shift toward increasing benefit as the risk of disease increases. For most diseases, and certainly for cancer and coronary heart disease, the risk increases with advancing age. So, all other things being equal, screening older people should be more likely to lead to net benefit than screening younger people. Of course, all other things are not equal as one ages. We know very little about the efficacy of screening in older persons, but advancing age brings changes that reduce the chance that the benefits of screening will exceed its harms. A risk factor in younger people may not be a risk factor in older persons. Cholesterol screening is a case in point. Cohort studies suggest that an increased serum cholesterol level is a weaker risk factor for coronary heart disease in older people and may not increase the risk in older men.1 Although treatment may reduce serum cholesterol levels in older people, the coronary death rate won't change if it is independent of the serum cholesterol level. The risk of disease may fall in older people. After age 65, the risk of cervical cancer is very low in monogamous women who have had consistently negative cervical cytology. Screening fails in older people in part because they die of other diseases before they can benefit from screening. A person's total mortality rate is the sum of the mortality rates of the patient's diseases and the patient's age-specific mortality rate. The age-specific mortality rate increases with age, reducing the overall impact of any reduction in disease-specific mortality rate, and the improvement in life expectancy from treating a disease shrinks steadily as a person ages from the seventh into the ninth decade.2 With benefit declining during advancing age, the balance of harms and benefits will usually shift in the direction of net harm, as the harms of follow-up testing and treatment tend to increase with advancing age. Many years of periodic screening may be required to yield a substantial difference in the mortality rate between screened and unscreened persons. In women aged 50 to 69 years, the breast cancer death rate does not change during the first four years of regular screening. After 4 years, the breast cancer death rate of screened women steadily diverges from the death rate of unscreened women, albeit slowly. The psychological benefits of screening may change as a person ages. Reassurance that one does not have cancer may mean less as a person ages and grows to accept the closeness of death. Screening may be increasingly burdensome as people age. Sensory and cognitive problems, physical disability, and difficulty getting transportation all increase the hardship of getting to the place where screening occurs. Are physicians alert to the possibility that the harms of screening older people with many comorbid illnesses might outweigh the benefits? Two articles in this issue indicate that physicians do fewer screening tests in older people and in sick people. The two articles complement one another. Kiefe and her colleagues measured the frequency of cervical and breast cancer screening as a function of the comorbidity score, an indicator of the number and severity of comorbid illnesses.3 The age range of the patients, 50 to 74 years, covers the period during which breast cancer screening is most effective and avoids the years after age 75, when advancing age alone might motivate less aggressive screening. Dr. Kiefe found that the screening frequency went down steadily with increasing comorbidity score, taking factors such as age into account. Burack and his colleagues focused on the effect of advancing age and tried to separate the effect of aging from that of worsening health.4 This study included women who were more than 50 years old and participated in a national, household-based health survey. The interviews provided information on their health status (good, fair, or poor) and limitations in activity (one or more limitations vs none). Mammography rates fell with advancing age and with worsening health status in univariate analyses, and age predicted mammography rates in multivariate analyses in which age and health status were predictor variables. In a subgroup analysis of women who reported good or better health, women aged years 75 or older had 40% lower mammography rates than women aged 50 to 64 years. These two studies strongly suggest that advancing age and comorbid illnesses are associated with less cancer screening in women. What is the reason? Physicians appear to take comorbidity into account when deciding about screening, as the decline in screening rates with increasing comorbidity occurs at ages when mammography is strongly recommended.3 The dearth of evidence-based recommendations for older women, however, could account for the reduction in screening in women aged 75 years or older. Perhaps physicians do a mental calculation of expected length of life and withhold screening from those with a short expected life span. This hypothesis could account for the effects of comorbidity and advancing age on screening rates. Alternatively, older women and sicker women may seek screening less aggressively. Perhaps older women are more likely than younger women to defer decisions about screening to their physicians. Are physicians right to be less aggressive in screening older people and sick people? Until there is evidence from good clinical trials, we will have to rely on indirect evidence to make patient-specific decisions. Here is a rule of thumb for deciding whether to start screening or to continue screening. First, determine the life expectancy for the patient's physiologic age (see Table 1 in reference 2), which is the period during which screening could be helpful. Second, determine how many years of screening are required before screened people have lower disease-specific mortality rate than unscreened people. This period is approximately 5 years when screening for breast cancer 5 or for colorectal cancer.6 Third, ask how the patient feels about screening, diagnosis, and treatment. If the patient will live long enough to experience the potential benefit from screening, would accept treatment, and would value the years that could be gained, screening may be appropriate. With this rule of thumb, we will occasionally find ourselves offering screening to a healthy, vigorous, 90-year-old person. Even for healthy older patients, most screening decisions are likely to be “close calls,” which makes talking with the patient about screening even more important. With enough discussion, the right decision about screening will become obvious.

The development of varenicline reflects new understanding of how nicotine acts to increase craving for cigarettes. Two studies recently published in the Journal of the American Medical Association ...

We have known for some time that fewer medical students and internal medicine residents are deciding on careers in primary care. As we try to transform primary care into a desirable career choice, ...

This issue features 2 position papers on reforming internal medicine residency education. Although the proposed reforms are visionary, far-reaching, and appealing, they lack a road map and the nece...

The scientific literature is a record of the search for truth. Publication of faked data diverts this search. The scientific community has a duty to warn people to ignore an article containing faked data and must try to prevent inadvertent citation of it. The scientific community accomplishes these tasks by publishing a retraction and linking it to the fraudulent article's citation in electronic indexes of the medical literature, such as PubMed. This mechanism is far from perfect, as shown by a case history of scientific fraud perpetrated by Eric Poehlman, PhD. His institution notified 3 journals that they had published tainted articles. Two journals failed to retract. The third journal retracted immediately, but other authors continued to cite the retracted article. Another duty of the scientific community is to verify the integrity of other articles published by the author of a fraudulent article. This task falls to the author's institution and requires coauthors to vouch for their article's integrity by convincing institutional investigators that the suspect author could not have altered the raw scientific data from their study. Two universities are currently investigating Poehlman's published research. Maintaining the integrity of the scientific literature requires governmental institutions that have the authority to investigate and punish guilty scientists and requires that research institutions investigate alleged fraud. It requires journal editors to issue a retraction when they learn that their journal has published a tainted article. It requires research institutions to accept their responsibility to investigate every article published by a scientist who has published even 1 fraudulent article. Finally, it requires authors to take pains to avoid citing retracted articles and to issue a correction when they inadvertently cite a retracted article.

This issue contains 2 articles about the management of suspected pulmonary embolism (PE). One shows that physicians frequently fail to use evidence-based diagnostic guidelines, especially when inte...

As the United States slides into a crisis of access to primary care, the results of the American Board of Internal Medicine–American College of Physicians survey, reported by Lipner and colleagues ...

In 2002, Annals published a systematic review of screening for prostate cancer. The value of screening depends on the effectiveness of treatment of early-stage prostate cancer. In 2002, the only we...

The cost of health care is one of the most serious problems facing the United States. Many factors drive health care costs, and their interrelationships are so complex that most people, whether in ...

In this issue, Cooper argues that the United States will have 200 000 fewer physicians than needed in 2020. Demographic and economic trends could increase the demand for physician services, but his...

In February 2002, the American Board of Internal Medicine Foundation, the American College of Physicians Foundation, and the European Federation of Internal Medicine published the Charter on Medica...