LETTERS

Annals of Internal Medicine COMMENTS AND RESPONSES

Disclaimer: The opinion expressed here reflects the positions and policies of the AASM and the author.

Diagnosis of Obstructive Sleep Apnea in Adults

Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L14-0594.

TO THE EDITOR: The American College of Physicians' (ACP's)

References

clinical practice guideline about the diagnosis of obstructive sleep apnea (OSA) in adults (1) addresses a prevalent and serious medical illness that deserves the attention of internists. Although ACP's clinical guideline and that of the American Academy of Sleep Medicine (AASM) share some similarities, substantial differences are of concern to the AASM. The ACP's recommendation to limit home sleep apnea testing to situations “when polysomnography [PSG] is not available for diagnostic testing” is overly restrictive and inconsistent with the AASM clinical guideline. Home sleep apnea testing interpreted by a sleep specialist in conjunction with a comprehensive sleep evaluation may be an equally viable diagnostic option in patients with a high pretest probability for at least moderate to severe OSA who do not have comorbid cardiopulmonary or neuromuscular disorders and in whom other sleep disorders are not a consideration (2). Under these conditions, a home sleep apnea test may be the most reasonable choice even when PSG is available. When these conditions are not met but sleep-disordered breathing is a consideration, we agree that PSG is the test of choice. Furthermore, the ACP guideline places an inordinate emphasis on sleepiness as the main reason for evaluation with sleep testing. In the WSC (Wisconsin Sleep Cohort) study, only 37% of patients with severe OSA (apnea– hypopnea index ≥30 events per hour) reported daytime sleepiness, which is 1 of many symptoms that may suggest that OSA should be included in the differential diagnosis (3). Other symptoms include witnessed apnea, snoring, nocturnal gasping or choking, nonrefreshing or disturbed sleep, nocturia, morning headaches, impaired concentration, memory loss, and decreased libido (4). Concurrent risk factors, such as obesity, retrognathia on examination, hypertension, or type 2 diabetes, should prompt consideration for sleep apnea testing; however, some of the other causes of sleepiness do not require sleep apnea testing and respond to specific interventions. A report of excessive sleepiness should prompt a comprehensive review of the patient's sleep schedule, questioning for auxiliary symptoms of narcolepsy, and consideration for sleep specialist referral if the cause is not apparent (5). It is critical to advance high-value care of patients with a sleep illness, such as OSA. Physicians should inquire for symptoms of sleep disturbances and specifically look for sleep apnea in patients belonging to high-risk populations, including those who do not report sleepiness. The AASM recognizes that internists play an important role in the management of patients with OSA, and we believe that collaborative relationships between sleep specialists and internists will undergird our efforts to improve public health by promoting healthy sleep. Timothy I. Morgenthaler, MD Mayo Clinic Center for Sleep Medicine, Mayo Clinic Rochester, Minnesota

1. Qaseem A, Dallas P, Owens DK, Starkey M, Holty JE, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Diagnosis of obstructive sleep apnea in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2014;161:210-20. [PMID: 25089864] doi:10.7326/M12-3187 2. Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, et al; Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5:263-76. [PMID: 19960649] 3. Young T, Finn L, Peppard PE, Szklo-Coxe M, Austin D, Nieto FJ, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep. 2008;31:1071-8. [PMID: 18714778] 4. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014. 5. Kushida CA, Littner MR, Morgenthaler T, Alessi CA, Bailey D, Coleman J Jr, et al. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep. 2005;28:499-521. [PMID: 16171294]

My candle burns at both ends; It will not last the night; But ah, my foes, and oh, my friends— It gives a lovely light. —Edna St. Vincent Millay TO THE EDITOR: We read with concern the ACP clinical guideline about the diagnosis of OSA (1). This guideline offers PSG as a solitary tool for sleep-related symptoms; the guideline's broad application could result in unnecessary testing and treatment. Polysomnography performed with current technologies and scored using the criteria recommended by the AASM in 2012 will yield an average apnea– hypopnea index that is 3-fold higher than that obtained with the equipment and scoring criteria available at the time of most of the studies cited to support this guideline. Flow changes are currently graded using a pressure-transduced air flow monitor—which is far more sensitive than the thermistor used in prior studies—and the new AASM guideline does not require oxygen desaturation to be present for a breathing event to be scored (2). In fact, a recent trial showed that the prevalence of an apnea– hypopnea index of 5 or more events per hour using the current criteria was 94.6% in a population with a “mild-moderate” pretest probability of OSA (3). This condition exists on a spectrum, and apnea– hypopnea index cutoffs are largely arbitrary. Given the changes in diagnosis, are we measuring clinically meaningful disease? What are the costs of overdiagnosis? Furthermore, the term “unexplained sleepiness” (which is pivotal in the guideline's first recommendation) is meaningful only when clinicians thoroughly understand the causes of sleepiness. The average physician receives approximately 2 hours of formal medical education on the evaluation of sleep disorders (4). This guideline fails to acknowledge that behaviorally induced insufficient sleep, insomnia, mood disorders, © 2015 American College of Physicians 455

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LETTERS the restless legs syndrome, and many other problems cannot be measured by PSG or treated with continuous positive airway pressure. We know from survey data that the average person in the United States effectively “burns the candle at both ends,” obtaining 6 hours and 40 minutes of sleep on the average workday (5). Recommending PSG for every patient whose sleepiness is “unexplained”—without also recommending qualitative and quantitative assessment of sleep duration—is ill-advised. We suggest that the ACP develop a comprehensive sleep– symptom guideline that encourages a more holistic evaluation of the patient who presents with sleepiness and focuses more attention on the limitations of PSG. Jordanna M. Hostler, MD David C. Hostler, MD, MPH Aaron B. Holley, MD Walter Reed National Military Medical Center Bethesda, Maryland Disclaimer: The views represented in this letter are those of the authors and do not reflect the policies of the U.S. Department of Defense or the U.S. Army.

Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L14-0593. References 1. Qaseem A, Dallas P, Owens DK, Starkey M, Holty JE, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Diagnosis of obstructive sleep apnea in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2014;161:210-20. [PMID: 25089864] doi:10.7326/M12-3187 2. Ruehland WR, Rochford PD, O’Donoghue FJ, Pierce RJ, Singh P, Thornton AT. The new AASM criteria for scoring hypopneas: impact on the apnea hypopnea index. Sleep. 2009;32:150-7. [PMID: 19238801] 3. Guerrero A, Embid C, Isetta V, Farre R, Duran-Cantolla J, Parra O, et al. Management of sleep apnea without high pretest probability or with comorbidities by three nights of portable sleep monitoring. Sleep. 2014;37:1363-73. [PMID: 25083017] doi:10.5665/sleep.3932 4. Rosen R, Mahowald M, Chesson A, Doghramji K, Goldberg R, Moline M, et al. The Taskforce 2000 survey on medical education in sleep and sleep disorders. Sleep. 1998;21:235-8. [PMID: 9595601] 5. National Sleep Foundation. 2008 Sleep in America Poll: Summary of Findings. (Prepared by WBA Research.) Washington, DC: National Sleep Foundation; 2008. Accessed at http://sleepfoundation.org/sites/default/files /2008%20POLL%20SOF.pdf on 8 September 2014.

IN RESPONSE: Dr. Morgenthaler objects to the focus on unexplained daytime sleepiness as the symptom prompting investigation and suggests that other symptoms, including snoring, nonrefreshing sleep, morning headaches, impaired concentration, memory loss, and decreased libido, should prompt an evaluation for OSA. We disagree; many patients who present to a primary care practice have at least 1 of these symptoms, and they all do not need sleep studies. Unexplained daytime sleepiness is the only symptom of OSA that evidence from randomized, controlled trials shows is responsive to treatment. Population studies suggest that high rates of subjective sleepiness in the general population are not associated with sleep apnea and are likely attributable to factors other than primary sleep disorders (1). Another study of the

general population has shown a high prevalence of sleep symptoms or disturbance among adults in the United States, with 75% reporting at least 1 sleep-related symptom (2). Furthermore, no evidence is available that shows that treatment specifically improves the particular outcomes previously mentioned; thus, knowledge of a diagnosis neither provides useful information to patients about their prognosis nor improves clinical outcomes. Although home monitors may be appropriate for some patients, current evidence shows that PSG is still the gold standard diagnostic test and should be the diagnostic test of choice when available. Hence, we disagree with Dr. Morgenthaler's comment that ACP's recommendation to use PSG as a first option for sleep testing is too restrictive. Although the AASM recommends using portable sleep monitors for patients with a high pretest probability for moderate to severe OSA, there is currently no accurate way to predict who is at high risk for OSA before doing a sleep study. The Agency for Healthcare Research and Quality evidence report (3) and the evidence review update showed poor diagnostic accuracy for screening questionnaires. Also, no current evidence shows that untreated mild OSA has any effect on mortality or morbidity. We agree with Dr. Hostler and colleagues that medical students generally receive inadequate training on sleep disorders. We suggest that physicians take a history to understand more about the patient's sleepiness rather than recommend sleep studies for all tired patients. We also suggest that patients who report inadequate hours of sleep be instructed to get more sleep before further investigation. Dr. Hostler and colleagues also point out that newer sensors are more sensitive than older forms of PSG, and we agree that, as technology changes, so do the implications for disease diagnoses. However, this statement is true for many fields of medicine. The update of the Agency for Healthcare Research and Quality evidence report included studies published since 2010 that evaluate the newer technologies. Nevertheless, similar to the data before 2010, the definitions and measurements of apnea or hypopnea were substantially heterogeneous among studies. In addition, the study that Dr. Hostler and colleagues cite (4)—which suggested a greater prevalence of OSA and potential overdiagnosis—was done in a patient population with mild to moderate clinical suspicion of OSA. Finally, their definition of hypopnea was liberal, which possibly accounted for a greater prevalence of OSA. Paul Shekelle, MD, PhD Greater Los Angeles Veterans Affairs Health Center and RAND Corporation Los Angeles, California Jon-Erik C. Holty, MD, MS Stanford University Stanford, California Thomas D. Denberg, MD, PhD Carilion Clinic Roanoke, Virginia

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LETTERS Amir Qaseem, MD, PhD, MHA American College of Physicians Philadelphia, Pennsylvania Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M12-3187. References 1. Kapur VK, Baldwin CM, Resnick HE, Gottlieb DJ, Nieto FJ. Sleepiness in patients with moderate to severe sleep-disordered breathing. Sleep. 2005;28: 472-7. [PMID: 16171292] 2. National Sleep Foundation. 2005 Sleep in America Poll: Summary of Findings. (Prepared by WBA Research.) Washington, DC: National Sleep Foundation; 2005. Accessed at http://sleepfoundation.org/sites/default/files/2005 _summary_of_findings.pdf on 16 October 2014. 3. Balk EM, Moorthy D, Obadan NO, Patel K, Ip S, Chung M, et al. Diagnosis and treatment of obstructive sleep apnea in adults. Comparative effectiveness review no. 32. AHRQ publication no. 11-EHC052-EF. (Prepared by Tufts Evidence-based Practice Center under contract 290-2007-100551.) Rockville, MD: Agency for Healthcare Research and Quality; 2011. Accessed at www .effectivehealthcare.ahrq.gov/ehc/products/117/683/CER32_SleepApnea _FinalReview_201108.pdf on 16 October 2014. 4. Guerrero A, Embid C, Isetta V, Farre R, Duran-Cantolla J, Parra O, et al. Management of sleep apnea without high pretest probability or with comorbidities by three nights of portable sleep monitoring. Sleep. 2014;37:1363-73. [PMID: 25083017] doi:10.5665/sleep.3932

Informed Decision Making About Prostate Cancer Screening TO THE EDITOR: One of the key facts that Vickers and col-

leagues (1) suggest presenting to patients to help them make an informed decision about prostate-specific antigen (PSA) screening is that “only a small proportion of men with prostate cancer die of the disease.” We do not believe that this statement accurately conveys the proportion of deaths attributable to prostate cancer in the context of counseling men considering PSA screening. Prostate cancer is the second most common cause of cancer death in men in Australia, the United States, the United Kingdom, and many countries in the European Union. Several countries outside the United States do not have high uptake of PSA screening, and a significant proportion of men with prostate cancer die of the disease. Even in the United States, self-reported PSA screening rates range from 59.4% (Hawaii) to 24.5% (New Hampshire) (2). Data from the Surveillance, Epidemiology, and End Results program support 10-year mortality rates of 6.1% for prostate cancer (patients diagnosed with localized disease) and 29.2% for other causes (3). This finding suggests that prostate cancer accounts for 17.2% of all deaths in men with localized disease in the first 10 years after diagnosis. Because these data relate to a group of men likely to have been screened, they are only part of the picture. An indication of the proportion of deaths due to prostate cancer in men who have not been screened is also required. Chowdhury and associates (4) report that prostate cancer was the cause of death in 49.8% of a United Kingdom cohort of 50 066 men. Localized prostate cancer was reported in 27 717 (55.4%), and prostate cancer accounted for 35.7% of all deaths in this group. In men younger than 65 years (n = 10 992), the all-cause mortality rate was 17.8%, with prostate www.annals.org

cancer recorded as the cause of death in 65.6%. Ten-year cumulative incidence plots present a consistent message. Our data from the South Australian Prostate Cancer Clinical Outcomes Collaborative identified that 577 (38.7%) reported deaths were attributable to prostate cancer among a cohort of 7018 men with this disease. Cumulative incidence of prostate cancer–specific mortality at 10 years was 15% and accounted for 36.5% of all deaths. In populations where PSA screening is less common, a somewhat larger proportion of men with prostate cancer may die of the disease. The advice that “a small proportion of men with prostate cancer die of the disease” should be stated cautiously because this declaration may lead to a decrease in screening rates and offers of curative treatment, which would potentially increase mortality. Michael E. O’Callaghan, BSc(Hons), PhD Repatriation General Hospital Adelaide, South Australia, Australia Ganessan Kichenadasse, MBBS Sina Vatandoust, MD Flinders University Adelaide, South Australia, Australia Kim Moretti, MBBS The University of Adelaide Adelaide, South Australia, Australia Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L14-0552.

References 1. Vickers AJ, Edwards K, Cooperberg MR, Mushlin AI. A simple schema for informed decision making about prostate cancer screening. Ann Intern Med. 2014;161:441-2. [PMID: 25222389] doi:10.7326/M14-0151 2. Sammon JD, Pucheril D, Diaz M, Kibel AS, Kantoff PW, Menon M, et al. Contemporary nationwide patterns of self-reported prostate-specific antigen screening. JAMA Intern Med. 2014;174:1839-41. [PMID: 25179266] doi: 10.1001/jamainternmed.2014.4117 3. Abdollah F, Sun M, Thuret R, Jeldres C, Tian Z, Briganti A, et al. A competing-risks analysis of survival after alternative treatment modalities for prostate cancer patients: 1988-2006. Eur Urol. 2011;59:88-95. [PMID: 20965646] doi:10.1016/j.eururo.2010.10.003 4. Chowdhury S, Robinson D, Cahill D, Rodriguez-Vida A, Holmberg L, Møller H. Causes of death in men with prostate cancer: an analysis of 50,000 men from the Thames Cancer Registry. BJU Int. 2013;112:182-9. [PMID: 23795786] doi:10.1111/bju.12212

IN RESPONSE: We stand by our original statement and are unclear with regard to the relevance of citing data from a largely unscreened population because the denominator will not include many men with biopsy-detectable cancer (that is, “men with prostate cancer”). The purpose of our statement is to reorient patients away from any perception that prostate cancer is generally fatal. Empirical data show that this perception is widespread (1). Dr. O’Callaghan and colleagues suggest that our statement will, of itself, “lead to a decrease in screening rates.” We find this concept questionable, especially because the stateAnnals of Internal Medicine • Vol. 162 No. 6 • 17 March 2015 457

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LETTERS ment is immediately followed by the assertion that “screening reduces the risk for prostate cancer death.” That said, our recommendation is a schema, not a script. It would be perfectly reasonable to adapt the schema to local circumstances or for individual clinicians to choose words based on what they believe best reflects the research evidence. For example, we cannot foresee any objection to stating “only a fraction of men with prostate cancer die of the disease” or “most men with prostate cancer die with, rather than of, the disease.” Andrew J. Vickers, PhD Memorial Sloan Kettering Cancer Center New York, New York Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-0151. Reference 1. Gigerenzer G, Mata J, Frank R. Public knowledge of benefits of breast and prostate cancer screening in Europe. J Natl Cancer Inst. 2009;101:1216-20. [PMID: 19671770] doi:10.1093/jnci/djp237

Treatment of Hepatitis C Virus Infection TO THE EDITOR: Kottilil and colleagues (1) state, “For the first time since the identification of hepatitis C virus (HCV) . . . communitywide eradication of HCV infection seems possible.” However, direct-acting antivirals have never been shown to prevent cirrhosis or hepatocellular carcinoma. Even if these agents effectively prevented these crucial complications of chronic HCV infection, the prevalence of cirrhosis and liver cancer is already increasing and is likely to do so continuously for decades. Internists may assume some responsibility for antiviral administration and monitoring adverse effects of drugs, but the potentially lethal complications of chronic HCV infection will likely need specialty input for the remainder of our professional lives.

Donald Venes, MD Pelican Bay State Prison Crescent City, California Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L14-0550. Reference 1. Kottilil S, Wright M, Polis MA, Masur H. Treatment of hepatitis C virus infection: is it time for the internist to take the reins? Ann Intern Med. 2014;161: 443-4. [PMID: 25222390] doi:10.7326/M14-0741

TO THE EDITOR: Kottilil and colleagues (1) raise issues about the future of HCV therapy. As they cite, more than 230 million persons are likely infected with HCV, and the number of persons found to be infected will increase with the updated recommendations from the U.S. Preventive Services Task Force (2). Treatment regimens have traditionally been wrought with adverse effects and dose adjustments. In the age of interferon-free regimens, patients tolerate therapy without many complications.

We agree that internists, subspecialists, and public health authorities will need to work in cooperation to treat persons with HCV infection. Although some patients may benefit from a hepatologist referral, we also agree that identification on the front line to properly triage these persons will be essential to success (3). Hepatologists have been the primary providers in treating HCV infection up to this time. The American Association for the Study of Liver Diseases has partnered with the Infectious Diseases Society of America to develop a Web site for up-to-date guidelines to direct treatment of HCV infection (www.hcvguidelines.org) because therapy is rapidly evolving. Further, specialty societies are creating educational materials geared toward first-line providers to support efforts to eradicate HCV infection. Internists are an integral part of the identification of patients with HCV infection, and coordinated efforts with the specialists who have a long history of treating this disease will be essential. Although now might be the time for internists to take the reins, we believe that it is important that they have the right specialist alongside to help guide these treatment plans. Of note, clinicians experienced in surmounting the hurdles of caring for and managing patients with mild chronic, advanced, and potentially fatal liver disease should provide guidance on expanding the pool of care providers. Neeral L. Shah, MD Virginia Kelly, RN Stephen H. Caldwell, MD University of Virginia Charlottesville, Virginia Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L14-0548.

References 1. Kottilil S, Wright M, Polis MA, Masur H. Treatment of hepatitis C virus infection: is it time for the internist to take the reins? Ann Intern Med. 2014;161: 443-4. [PMID: 25222390] doi:10.7326/M14-0741 2. Moyer VA; U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159:349-57. [PMID: 23798026] doi:10.7326 /0003-4819-159-5-201309030-00672 3. Mitruka K, Thornton K, Cusick S, Orme C, Moore A, Manch RA, et al; Centers for Disease Control and Prevention (CDC). Expanding primary care capacity to treat hepatitis C virus infection through an evidence-based care model— Arizona and Utah, 2012-2014. MMWR Morb Mortal Wkly Rep. 2014;63:393-8. [PMID: 24807237]

TO THE EDITOR: I read Kottilil and colleagues' article (1) with

great interest. This comment is to generate thought, not simply to be contrary. I have my clinical niche and certainly encourage other internists to aggressively pursue their interests, including HCV infection. I enjoy the opportunities to quarterback for complex cases. My concern, to use 1 example, is that private insurers, Medicare, accountable care organizations, and patient-centered medical home initiatives expect internists to act as data clerks for every aspect of care for patients with a diabetes code in the electronic health record. I am faulted when the patient has an endocrinologist who already addresses the many diabetes mellitus checkboxes but does

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LETTERS not use my electronic health record and am penalized by the National Committee for Quality Assurance certification program when I do not allocate staff to call the ophthalmologist who did not bother to send me a letter documenting the eye examination. Such an initiative as “the time . . . is now” for us to treat HCV infection must be accompanied by a plan for a comprehensive, system-based infrastructure supported by the companies claiming to be responsible for patient well-being, not just a way for us to get more patients into our office slots and increase the preapproval paperwork burden for our staff. If this issue will overwhelm subspecialists, then practicing internists should be supported as we are expected to handle many more issues during an office visit. Michael P. Carson, MD Jersey Shore University Medical Center Neptune, New Jersey Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=L14-0549. Reference 1. Kottilil S, Wright M, Polis MA, Masur H. Treatment of hepatitis C virus infection: is it time for the internist to take the reins? Ann Intern Med. 2014;161: 443-4. [PMID: 25222390] doi:10.7326/M14-0741

IN RESPONSE: Dr. Venes correctly states that “direct-acting

antivirals have never been shown to prevent cirrhosis or hepatocellular carcinoma.” Indeed, the long-term effects of new drugs on the complications of HCV infection merit careful study to be certain that their apparent benefits are fully realized. The experience with virologic cure after interferonbased therapies suggests that cure of HCV infection using direct-acting antivirals will plausibly prevent such sequelae (1, 2). Dr. Venes also observes that, even if direct-acting antivirals prevent complications, we will have to manage many patients in the current cohort of HCV-infected persons who do not access care or who already have advanced liver disease. This observation is correct but underscores the need to treat as many patients with HCV infection as possible now so that we decrease progression of HCV infection–related liver disease to the greatest extent possible. Dr. Shah and colleagues emphasize the importance of internists gaining knowledge and experience in the management of HCV infection and collaborating with subspecialists. We wholeheartedly agree. Professional organizations are accelerating their efforts to have continuing medical education for providers with different experiential backgrounds and to offer guidance documents and tutorials that are up to date, focused, and practical. The guidance Web site (www .hcvguidelines.org) that we and Dr. Shah and colleagues cited (and that 2 of us coauthored) has had more than 150 000 unique visitors and almost 1 million page views since its inauguration on 29 January 2014. Internists are highly skilled at working with subspecialists to provide excellent management for patients whose problems are beyond their expertise or scope of practice. Partnerships between primary care providers and subspecialists are vital for all aspects of medicine, including management of HCV infection. www.annals.org

Dr. Carson points out with passion the plight of internists in the current era. We are all required by payers and regulatory agencies to do more. The ability to support electronic health records and afford to pay staff who have the time to respond to these diverse demands is challenged by declining reimbursement. More important, such demands can rob us of the deep satisfaction of caring for the whole patient. We do not mean to suggest that it is practical for every internist to become an expert in HCV infection, but internists can certainly identify infected patients, enhance their linkage to care, and cure a large fraction of these patients. Shyam Kottilil, MD, PhD Institute of Human Virology, University of Maryland Baltimore, Maryland Mary Wright, MD, MPH Michael A. Polis, MD, MPH National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, Maryland Henry Masur, MD National Institutes of Health Bethesda, Maryland Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M14-0741. References 1. Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122:1303-13. [PMID: 11984517] 2. Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, Albrecht J. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C. J Hepatol. 2001;34:730-9. [PMID: 11434620]

Low-Dose Computed Tomography Screening for Lung Cancer TO THE EDITOR: As Wiener described, a Medicare advisory

panel recommended against coverage of low-dose computed tomography (LDCT) for Medicare beneficiaries. Many professional organizations recommend LDCT provided that it is undertaken as a structured program in centers with considerable expertise in lung cancer care (1). Wiener suggests that the optimal way for the Centers for Medicare & Medicaid Services to proceed may be to offer coverage for LDCT screening only when performed by facilities that are certified as comprehensive, patient-centered programs. The Building Trades National Medical Screening Program uses a regionalized approach to lung cancer screening, linking local providers with a regional cancer center of excellence. Under authorization from Congress, this program has been screening workers employed at U.S. Department of Energy atomic weapons facilities for occupational diseases since 1999. These persons are at significantly increased risk for chronic obstructive pulmonary disease and lung cancer mortality (3, 4) and are likely to live in rural areas that are not Annals of Internal Medicine • Vol. 162 No. 6 • 17 March 2015 459

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LETTERS served by medical providers with the kinds of expertise recommended for LDCT screening. The Building Trades National Medical Screening Program partnered with the Seattle Cancer Care Alliance (SCCA)—the comprehensive cancer center for the Pacific Northwest—to provide early lung cancer detection for persons from the Hanford Nuclear Reservation, located 200 miles from Seattle, while adhering to the National Comprehensive Care Network guidelines for eligibility and diagnostic evaluation (2). A local SCCA affiliate, Kadlec Regional Medical Center, administers the LDCT, and a thoracic radiologist at the University of Washington interprets the results. A multidisciplinary nodule board reviews suspicious nodules. Patients who require evaluation beyond repeated LDCT are invited to come to the SCCA; any surgical resection is done by the University of Washington cardiothoracic surgeons. The SCCA provides a smoking cessation program. To encourage care at the SCCA, the program facilitates travel. As of September 2014, we have enrolled 184 participants from the Hanford Nuclear Reservation; 37 had indeterminate nodules (2), 17 had suspicious nodules, 5 have been diagnosed with lung cancer, and 94 have been referred for evaluation of medical findings other than lung cancer. Those with lung cancer were generally agreeable to travel for specialty care; 4 stage IA adenocarcinomas were removed with curative intent at the University of Washington. The fifth person opted not to come to the SCCA and was eventually diagnosed with stage IV squamous cell carcinoma. We believe that this model can be expanded to offer LDCT screening at comprehensive, high-quality regional cancer centers to all persons at high risk for lung cancer. Laura S. Welch, MD CPWR: The Center for Construction Research and Training and the Division of Pulmonary and Critical Care Medicine Silver Spring, Maryland David Madtes, MD University of Washington Seattle, Washington Knut Ringen, DrPH CPWR: The Center for Construction Research and Training and the Division of Pulmonary and Critical Care Medicine Silver Spring, Maryland Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L14-0557. References 1. Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the U.S. Preventive Services Task Force recommendation. Ann Intern Med. 2013;159:411-20. [PMID: 23897166] doi:10.7326/0003 -4819-159-6-201309170-00690 2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Lung Cancer Screening. Version 1.2015. Fort Washington, PA: National Comprehensive Cancer Network; 2014. 3. Dement JM, Ringen K, Welch LS, Bingham E, Quinn P. Mortality of older construction and craft workers employed at Department of Energy (DOE) nuclear sites. Am J Ind Med. 2009;52:671-82. [PMID: 19670258] doi:10.1002 /ajim.20729

4. Dement JM, Welch L, Ringen K, Bingham E, Quinn P. Airways obstruction among older construction and trade workers at Department of Energy nuclear sites. Am J Ind Med. 2010;53:224-40. [PMID: 20025074] doi:10.1002 /ajim.20792

IN RESPONSE: We congratulate Dr. Welch and colleagues on their work to develop a regional lung cancer screening center serving high-risk persons living in rural communities. In particular, we applaud the incorporation of a smoking cessation program, the use of predetermined criteria for LDCT screening eligibility and nodule evaluation, and the involvement of multiple disciplines in deciding how to evaluate screendetected nodules. However, these elements are not in themselves sufficient for a comprehensive LDCT screening program. Guidelines for LDCT screening also recommend shared decision making about the benefits and harms of screening and the maintenance of a registry of persons who have had screening (1, 2). Indeed, these additional elements are required for Medicare coverage of LDCT screening (3). Careful design and implementation of comprehensive LDCT screening programs, including these elements, should help optimize the balance of benefits and harms for persons being screened for lung cancer (4). However, further study of these programs as they are implemented in the real world is essential to ensure that lung cancer screening is safe, effective, and affordable.

Renda Soylemez Wiener, MD, MPH The Pulmonary Center, Boston University School of Medicine Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-1352. References 1. Detterbeck FC, Mazzone PJ, Naidich DP, Bach PB. Screening for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143: e78S-92S. [PMID: 23649455] doi:10.1378/chest.12-2350 2. Moyer VA; U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160:330-8. [PMID: 24378917] doi:10.7326/M13-2771 3. Centers for Medicare & Medicaid Services. Decision memo for screening for lung cancer with low dose computed tomography (LDCT) (CAG-00439N). 5 February 2015. Accessed at www.cms.gov/medicare-coverage-database /details/nca-decision-memo.aspx?NCAId=274 on 6 February 2015. 4. Mazzone P, Powell CA, Arenberg D, Bach P, Detterbeck F, Gould M, et al. Components necessary for high quality lung cancer screening: American College of Chest Physicians and American Thoracic Society policy statement. Chest. 2014. [PMID: 25356819] doi:10.1378/chest.14-2500

Three Nonnucleoside Reverse Transcriptase Inhibitor–Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1 TO THE EDITOR: A design characteristic in Lennox and col-

leagues' trial (1) allowed patients to switch the third antiretroviral compound within the ACTG (AIDS Clinical Trials Group) A5257 open-label trial; this method is distinct from that of historical randomized clinical comparisons. The aim of this

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LETTERS protocol specification may have been to enable an antiretroviral therapy switch for patients facing nonserious adverse events, thus approaching a real-life clinical setting. A prerequisite for an unbiased observation is the free dispensing of all administered study drugs. However, a booster of ritonavir, 100 mg/d, was not provided for participants randomly assigned to a protease inhibitor regimen within the study, and whether affected patients were reimbursed for these costs remains unclear. Second, atazanavir maintenance was most likely disadvantaged by the distinct design characteristic, because cosmetically adverse hyperbilirubinemia has previously not been a typical reason for atazanavir cessation (2– 4). Physicians and affected patients had an interest to carry out the per protocol–allowed switch toward raltegravir, “killing 2 birds with 1 stone” and allowing patients to save money from a ritonavir prescription and overcome atazanavir-related hyperbilirubinemia. Preferred recruitment of impoverished, uninsured women may have further aggravated this circumstance, as previously described (5). Because of these limitations, any consequences of the trial on treatment guideline modifications should be evaluated with caution. Christoph Stephan, MD Goethe-University Hospital Frankfurt, Germany Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L14-0591.

References 1. Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, et al; ACTG A5257 Team. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461-71. [PMID: 25285539] doi:10.7326/M14-1084 2. Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, et al; CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372:646-55. [PMID: 18722869] doi:10.1016/S0140-6736(08)61081-8 3. Riddler SA, Haubrich R, DiRienzo AG, Peeples L, Powderly WG, Klingman KL, et al; AIDS Clinical Trials Group Study A5142 Team. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358:2095106. [PMID: 18480202] doi:10.1056/NEJMoa074609 4. Daar ES, Tierney C, Fischl MA, Sax PE, Mollan K, Budhathoki C, et al; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 2011;154:445-56. [PMID: 21320923] doi:10.7326/0003-4819-154-7201104050-00316 5. Sax PE, Landovitz RJ. Selecting an initial ART regimen: lessons from ACTG 5257. Medscape. 11 April 2014. Accessed at www.medscape.com/viewarticle /823164 on 23 June 2014.

TO THE EDITOR: In their randomized, controlled trial, Lennox

and colleagues (1) reported that discontinuations of atazanavir and ritonavir due to lack of tolerability were significantly more common than discontinuations of darunavir and ritonavir or raltegravir. This effect was mainly driven by atazanavirinduced jaundice and hyperbilirubinemia. This study is charwww.annals.org

acterized by an innovative design in the field of HIV therapy because patients were allowed to change treatment groups if they were intolerant to randomly assigned treatment and because the time to discontinuation due to toxicity (as assessed and reported by the treating physician) was used as a predefined tolerability end point. Although we understand the logic behind this attempt to reproduce “real-life” conditions, we question whether this reproduction is within the possibilities and scope of a randomized, controlled trial. In clinical practice, changing an antiretroviral regimen is a free and mutual decision by physicians and patients and is determined by many factors that are not present or accounted for during a randomized, controlled trial, such as socioeconomic characteristics, previous knowledge and experience with the drugs, peer influences, the physician–patient relationship, and the availability of all licensed alternative drugs. Last but not least, important determinants of physician prescriptions are patients' expectations and, even more, physicians' opinions on patients' expectations (2). Therefore, the “threshold” of the tolerability of drug-related adverse effects varies not only among patients but also among physicians and may change over time within the same patient or physician. Also, ascribing a treatment switch to a single cause (“toxicity”) can be difficult and, ultimately, subjective. For these reasons, we believe that assessing “discontinuation due to toxicity” as a component of a randomized clinical trial end point in the absence of a predefined definition of tolerability and toxicity can be challenging. In this respect, the data on treatment discontinuation rates obtained from observational cohorts of unselected patients are probably closer to reality. Giuseppe Lapadula, MD, PhD Andrea Gori, MD University Milano-Bicocca Milan, Italy Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L14-0590. References 1. Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, et al; ACTG A5257 Team. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461-71. [PMID: 25285539] doi:10.7326/M14-1084 2. Cockburn J, Pit S. Prescribing behaviour in clinical practice: patients' expectations and doctors' perceptions of patients' expectations—a questionnaire study. BMJ. 1997;315:520-3. [PMID: 9329308]

IN RESPONSE: Dr. Stephan proposes a potential bias against ritonavir-boosted atazanavir due to the necessity to reimburse ritonavir copayments. He also suggests that efforts to ensure adequate representation of women may have enriched the study for impoverished participants predisposed to discontinue ritonavir-containing regimens to avoid costs. We did not target any particular socioeconomic subgroup of women for enrollment nor have we suggested that we did so. The potential biases associated with ritonavir use during the study were anticipated and addressed during trial design. As noted in the article, all participants not receiving ritonavir from a federal Annals of Internal Medicine • Vol. 162 No. 6 • 17 March 2015 461

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LETTERS insurance program were reimbursed in a timely manner. Furthermore, the protocol encouraged sites to make within-class regimen switches; as a result, 72% of those who discontinued ritonavir-boosted atazanavir switched to ritonavir-boosted darunavir. Dr. Stephan also cites 3 studies in which hyperbilirubinemia was not a common reason for atazanavir cessation. One of these studies (ACTG A5142) did not include atazanavir. Another study (ACTG A5202) placed stringent limitations on regimen switching because it compared not only ritonavirboosted atazanavir with efavirenz but also separate nucleoside reverse transcriptase inhibitor combinations. The third study (CASTLE [Comparing the Antiviral Efficacy and Safety of Atazanavir/Ritonavir With Lopinavir/Ritonavir, Each in Combination With Fixed-Dose Tenofovir–Emtricitabine in HIV-1– Infected Treatment-Naive Subjects]) compared a 3-pill, oncedaily boosted atazanavir regimen with a 6-pill, twice-daily boosted lopinavir regimen, a design that may have discouraged regimen changes. Our study shows that some participants who develop cosmetically intolerable hyperbilirubinemia will choose to change therapy if equally effective and convenient options are available. We agree with Drs. Lapadula and Gori that careful planning is essential for studies that include discontinuation of treatment due to toxicity as an end point. For this reason, toxicity end points in our study were predefined and strictly categorized according to the Division of AIDS toxicity table. Tolerability was also strictly defined as the intent of the participant to discontinue the treatment because of toxicity. We believe that participant-driven tolerability discontinuations for toxicity are a necessary and useful measure for comparing commercially available medications. However, we agree with Drs. Lapadula and Gori that study of observational cohorts can further inform results from randomized studies. In a recent analysis, 11.7% of Korean patients discontinued atazanavir because of jaundice (1) compared with 7.8% of participants in our study. This rate of discontinuation took place despite Koreans' having a lower frequency of a polymorphism in uridine 5’-diphosphate glucuronosyltransferase 1A1 associated with atazanavir-induced hyperbilirubinemia than the HIV-1–infected population in the United States (2, 3). Our study population may therefore have facilitated our ability to detect this important tolerability difference between ritonavir-boosted protease inhibitors recommended by the U.S. Department of Health and Human Services. Jeffrey L. Lennox, MD Emory University School of Medicine Atlanta, Georgia Raphael J. Landovitz, MD, MSc Center for Clinical AIDS Research and Education, University of California, Los Angeles Los Angeles, California Heather J. Ribaudo, PhD Harvard School of Public Health Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-1084.

References 1. Choe PG, Park WB, Song KY, Bang JH, Kim ES, Park SW, et al. Effect of ritonavir-boosting on atazanavir discontinuation due to jaundice in HIVinfected Koreans. Infect Chemother. 2012;44:175-9. 2. Park WB, Choe PG, Song KH, Jeon JH, Park SW, Kim HB, et al. Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDP-glucuronosyltransferase 1A1*28 allele frequency. Clin Infect Dis. 2010;51:101-6. [PMID: 20504240] doi:10.1086/653427 3. Hall D, Ybazeta G, Destro-Bisol G, Petzl-Erler ML, Di Rienzo A. Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates. Pharmacogenetics. 1999;9:591-9. [PMID: 10591539]

OBSERVATION

Mercury Poisoning Presenting as Sporadic Creutzfeldt–Jakob Disease: A Case Report Background: Mercury poisoning is a rare and highly disabling condition (1). Because early chelation therapy can decrease serum mercury concentrations, identifying mercury poisoning in its earliest stage is important. Objective: To alert clinicians that mercury poisoning may be confused with sporadic Creutzfeldt–Jakob disease (CJD). Case Report: A 42-year-old male office clerk who lived alone and was in good health except for well-controlled hypertension began having progressive memory disturbance that continued for 5 months. He was irritable and had difficulty recalling recent conversations. He also reported numbness and tingling in the limbs, slow movement, and sleepiness. A magnetic resonance image (MRI) of the brain at another hospital 3 months after symptoms began showed striking, relatively symmetric, high-intensity, diffusion-weighted imaging signals in the cortex without gadolinium enhancement (Figure, panels A and B). An electroencephalogram showed slow overall activity. The clinical course and MRI suggested CJD despite unremarkable results on cerebrospinal fluid studies with normal 14-3-3 protein levels, and the sporadic form of the disease was diagnosed because there was no mutation in the PRNP gene. He was treated with intravenous methylprednisolone, 500 mg/d for 7 days, followed by oral prednisone tapering. His symptoms did not improve, and his disability accelerated 1 week before admission to our hospital in March 2012. Neurologic examination found prominent cognitive impairment and extrapyramidal features. His Folstein Mini-Mental State Examination score was 20 out of 30. He had bilateral symmetric bradykinesia, cogwheel rigidity in the upper limbs, and impaired finger–nose coordination. An MRI of the brain revealed hyperintense diffusion-weighted imaging signals and hypointense apparent diffusion coefficient signals in the caudate nucleus and the frontal, temporal, and occipital cortices (Figure, panels C and D). Results of screening tests for connective tissue disease and blood titers for rapid plasma reagin and voltage-gated potassium-channel and paraneoplastic antibodies were normal. An electromyogram revealed remarkably decreased sensory amplitudes in the limbs. Screening tests for heavy metals found a blood mercury level of 76.3 nmol/L (levels fluctuate with dietary intake and other

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LETTERS Figure. Magnetic resonance image of the brain.

Yi Tang, MD, PhD Xiangbo Wang, MD Jianping Jia, MD, PhD Xuan Wu Hospital, Capital Medical University, Beijing Neurology Consultation Center Beijing, China Note: All authors contributed equally to this work. Grant Support: By the National Science Foundation of China (30900478), the New-Star of Science and Technology supported by Beijing Metropolis (2010B053), and the Beijing Natural Science Foundation (7102072). Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L14-0348. References

A and B. Striking, relatively symmetric, bilateral, cortical gray matter involvement based on diffusion-weighted imaging and fluidattenuated inversion recovery images 3 mo after symptom onset. C and D. Hyperintense diffusion-weighted imaging signals and hypointense apparent diffusion coefficient signals in subcortical gray matter (caudate nucleus) and cortical gray matter 5 mo after symptom onset. E. No significant improvement on diffusion-weighted imaging after chelation therapy. F. Brain atrophy at 2-y follow-up.

acute exposures, and asymptomatic persons can have levels much higher than these) and a urinary mercury level of 109.2 nmol/L (reference range, 0.0 to 12.5 nmol/L; urine levels are more reliable for identifying clinically meaningful exposures). We asked additional questions and learned that the patient broke a mercury sphygmomanometer in bed several days before symptom onset and cleaned the spilled mercury the following day with a whisk broom. We diagnosed elemental mercury poisoning and administered the chelating agent sodium 2,3-dimercapto-1propanesulfonic acid. Numbness and tingling decreased substantially, memory and movement improved slightly, but MRI did not show improvement (Figure, panel E). Follow-up evaluation 2 years after discharge found persistent cognitive impairment and bradykinesia with a blood mercury level of 2.5 nmol/L, a urinary mercury level of 5.5 nmol/L, and sustained damage on MRI (Figure, panel F). Discussion: Elemental mercury poisoning is rare, and inhalation of mercury vapor is the major route (1, 2). The only previous report with neuroimaging involved a 10-year-old child with isolated hyperintense lesions (3). We report what we believe to be the first case with neuroimaging studies of elemental mercury poisoning in an adult. These images show widely symmetric cortical and subcortical gray matter involvement. We are not surprised that sporadic CJD was the initial diagnosis given the combination of subacute cognitive impairment, Parkinsonian symptoms, and linear lesions in the bilateral cerebral cortex and the caudate nucleus (4), although other conditions have been reported to mimic sporadic CJD, including neurodegenerative diseases and antibodymediated encephalitis (5). Clinicians should consider elemental mercury poisoning in patients suspected of having sporadic CJD. www.annals.org

1. Clarkson TW, Magos L, Myers GJ. The toxicology of mercury— current exposures and clinical manifestations. N Engl J Med. 2003;349:1731-7. [PMID: 14585942] 2. Asano S, Eto K, Kurisaki E, Gunji H, Hiraiwa K, Sato M, et al. Review article: acute inorganic mercury vapor inhalation poisoning. Pathol Int. 2000;50:16974. [PMID: 10792779] 3. Abbaslou P, Zaman T. A Child with elemental mercury poisoning and unusual brain MRI findings. Clin Toxicol (Phila). 2006;44:85-8. [PMID: 16496500] 4. Puoti G, Bizzi A, Forloni G, Safar JG, Tagliavini F, Gambetti P. Sporadic human prion diseases: molecular insights and diagnosis. Lancet Neurol. 2012; 11:618-28. [PMID: 22710755] doi:10.1016/S1474-4422(12)70063-7 5. Murray K. Creutzfeldt-Jacob disease mimics, or how to sort out the subacute encephalopathy patient. Pract Neurol. 2011;11:19-28. [PMID: 21239650] doi: 10.1136/jnnp.2010.235721

CORRECTIONS Correction: Combination Antifungal Therapy for Invasive Aspergillosis A recent article (1) had an error in Appendix Table 2. The percentage of GM antigen positivity only in patients receiving combination therapy should be 80%, not 15% as reported. This has been corrected in the online version. Reference 1. Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015;162:81-9. [PMID: 25599346] doi:10.7326/M13 -2508

Correction: The Benefits of Detecting and Treating Mild Hypertension Sundstro¨m and colleagues' analysis included patients at a mean age of 63.5 years, not 18 to 60 years as originally stated in the accompanying editorial (1). This has been corrected in the online version. Reference 1. Wright JT Jr. The benefits of detecting and treating mild hypertension: what we know, and what we need to learn. Ann Intern Med. 2015;162:233-4. [PMID: 25531681] doi:10.7326/M14-2836 Annals of Internal Medicine • Vol. 162 No. 6 • 17 March 2015 463

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Diagnosis of obstructive sleep apnea in adults.

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