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Clinical Guidelines | 
George F. Sawaya, MD; Shalini Kulasingam, PhD; Thomas Denberg, MD, PhD; and Amir Qaseem, MD, PhD, MHA, for the Clinical Guidelines Committee of the American College of Physicians*
Description:The purpose of this best practice advice article is to describe the indications for screening for cervical cancer in asymptomatic, average-risk women aged 21 years or older. Methods:The evidence reviewed in this work is a distillation of relevant publications (including systematic reviews) used to support current guidelines. Best Practice Advice 1:Clinicians should not screen average-risk women younger than 21 years for cervical cancer. Best Practice Advice 2:Clinicians should start screening average-risk women for cervical cancer at age 21 years once every 3 years with cytology (cytologic tests without human papillomavirus [HPV] tests). Best Practice Advice 3:Clinicians should not screen average-risk women for cervical cancer with cytology more often than once every 3 years. Best Practice Advice 4:Clinicians may use a combination of cytology and HPV testing once every 5 years in average-risk women aged 30 years or older who prefer screening less often than every 3 years. Best Practice Advice 5:Clinicians should not perform HPV testing in average-risk women younger than 30 years. Best Practice Advice 6:Clinicians should stop screening average-risk women older than 65 years for cervical cancer if they have had 3 consecutive negative cytology results or 2 consecutive negative cytology plus HPV test results within 10 years, with the most recent test performed within 5 years. Best Practice Advice 7:Clinicians should not screen average-risk women of any age for cervical cancer if they have had a hysterectomy with removal of the cervix.
Topics: cervical cancer screening, best practice, american college of physicians
Summaries for Patients | 
Topics: cervical cancer screening
Reviews | 
Eliano Pio Navarese, MD, PhD; Michalina Kołodziejczak, MD; Volker Schulze, MD; Paul A. Gurbel, MD; Udaya Tantry, PhD; Yingfeng Lin, MD; Maximilian Brockmeyer, MD; David E. Kandzari, MD; Julia M. Kubica, MD; Ralph B. D'Agostino Sr., PhD; Jacek Kubica, MD, PhD; Massimo Volpe, MD; Stefan Agewall, MD; Dean J. Kereiakes, MD; and Malte Kelm, MD
Background:Guidelines recommend statins as first-line therapy for dyslipidemia. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) are a new lipid-lowering approach. Purpose:To assess the efficacy and safety of PCSK9 antibodies in adults with hypercholesterolemia. Data Sources:MEDLINE, PubMed Central, and Google Scholar; conference proceedings; and the ClinicalTrials.gov registry through 4 April 2015. Study Selection:Phase 2 or 3 randomized, controlled trials (RCTs) comparing treatment using PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia. Data Extraction:Two investigators independently extracted data on study characteristics and lipid and clinical outcomes, and rated risk of bias of trials. Prespecified primary end points were all-cause and cardiovascular mortality. Data Synthesis:Twenty-four RCTs comprising 10 159 patients were included. Compared with no antibody, treatment with PCSK9 antibodies led to marked reductions in low-density lipoprotein cholesterol levels (mean difference, −47.49% [95% CI, −69.64% to −25.35%]; P < 0.001] and other atherogenic lipid fractions, and it reduced all-cause mortality (odds ratio [OR], 0.45 [CI, 0.23 to 0.86]; P = 0.015; heterogeneity P = 0.63; I2 = 0%) and cardiovascular mortality (OR, 0.50 [CI, 0.23 to 1.10]; P = 0.084; heterogeneity P = 0.78; I2 = 0%). The rate of myocardial infarction was significantly reduced with use of PCSK9 antibodies (OR, 0.49 [CI, 0.26 to 0.93]; P = 0.030; heterogeneity P = 0.45; I2 = 0%), and increases in the serum creatine kinase level were reduced (OR, 0.72 [CI, 0.54 to 0.96]; P = 0.026; heterogeneity P = 0.65; I2 = 0%). Serious adverse events did not increase with administration of PCSK9 antibodies. Limitations:Results were derived from study-level data rather than patient-level data, and clinical outcome data are rare. Conclusion:PCSK9 antibodies seem to be safe and effective for adults with dyslipidemia. Primary Funding Source:CRC 1116 Masterswitches in Myocardial Ischemia, German Research Council DFG.
Topics: ldl cholesterol lipoproteins, hypercholesterolemia, antibodies, pcsk9 gene, surrogate endpoints, myocardial infarction, adverse event, statins, ezetimibe, follow-up
Editorials | 
Miguel Cainzos-Achirica, MD; Seth S. Martin, MD, MHS; John E. Cornell, PhD, Associate Editor, Statistics; Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor; and Eliseo Guallar, MD, DrPH, Associate Editor, Statistics
In recent years, many monoclonal antibodies, including evolocumab, alirocumab, and bococizumab, were developed as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that lower low-density lipoprotein (LDL) cholesterol by disrupting the interaction between PCSK9 and the LDL receptor. In this issue, a meta-analysis provides important preliminary information on clinical outcomes as the U.S. Food and Drug Administration considers approval of PCSK9 inhibitors. The editorialists voice cautious enthusiasm but note that confirmation of these findings in long-term, ongoing, pivotal trials with prespecified cardiovascular disease end points and monitoring of adverse events are needed to establish the role of these novel agents in disease prevention.
Topics: lipids, pcsk9 gene
Medicine and Public Issues | 
Emilio Dirlikov, PhD; Mario Raviglione, MD; and Fabio Scano, MD
Since 1990, progress has been made toward global tuberculosis (TB) control, as measured by targets set for 2015. However, TB remains a major threat to health around the world. In 2013, there were an estimated 11 million prevalent cases, and an estimated 9.0 million incident cases occurred globally. Approximately 1.5 million deaths were caused by TB, including 360 000 among people living with HIV. Substantial challenges threaten future control efforts. These include multidrug-resistant forms and co-infection with HIV, as well as other factors, such as the increased prominence of noncommunicable diseases and adverse socioeconomic conditions. Beyond 2015, TB control must be seen as both a public health imperative unto itself and a vital component of economic development plans. To that end, control strategies should exploit technical and operational innovations to improve TB control and care and should promote universal health coverage and social protection mechanisms to expand access to essential prevention, diagnostics, and treatment services while avoiding catastrophic costs incurred by patients.
Topics: tuberculosis
Original Research | 
Stefan Zeuzem, MD; Reem Ghalib, MD; K. Rajender Reddy, MD; Paul J. Pockros, MD; Ziv Ben Ari, MD; Yue Zhao, PhD; Deborah D. Brown, BS; Shuyan Wan, PhD; Mark J. DiNubile, MD; Bach-Yen Nguyen, MD; Michael N. Robertson, MD; Janice Wahl, MD; Eliav Barr, MD; and Joan R. Butterton, MD
Background:Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection. Objective:To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients. Design:Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467) Setting:60 centers in the United States, Europe, Australia, Scandinavia, and Asia. Patients:Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection. Intervention:Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy. Measurements:Proportion of patients in immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups. Results:Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, −5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%). Limitation:The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections. Conclusion:Grazoprevir–elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infections. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection. Primary Funding Source:Merck & Co.
Topics: hepatitis c, chronic, therapy naive, grazoprevir, elbasvir, genotype, combined modality therapy, ribavirin
Original Research | 
Mildred K. Cho, PhD; David Magnus, PhD; Melissa Constantine, PhD, MPAff; Sandra Soo-Jin Lee, PhD; Maureen Kelley, PhD; Stephanie Alessi, JD; Diane Korngiebel, DPhil; Cyan James, PhD; Ellen Kuwana, MS; Thomas H. Gallagher, MD; Douglas Diekema, MD, MPH; Alexander M. Capron, LLB; Steven Joffe, MD, MPH; and Benjamin S. Wilfond, MD
Background:The U.S. Office for Human Research Protections has proposed that end points of randomized trials comparing the effectiveness of standard medical practices are risks of research that would require disclosure and written informed consent, but data are lacking on the views of potential participants. Objective:To assess attitudes of U.S. adults about risks and preferences for notification and consent for research on medical practices. Design:Cross-sectional survey conducted in August 2014. Setting:Web-based questionnaire. Patients:1095 U.S. adults sampled from an online panel (n = 805) and an online convenience river sample (n = 290). Measurements:Attitudes toward risk, informed consent, and willingness to participate in 3 research scenarios involving medical record review and randomization of usual medical practices. Results:97% of respondents agreed that health systems should evaluate standard treatments. Most wanted to be asked for permission to participate in each of 3 scenarios (range, 75.2% to 80.4%), even if it involved only medical record review, but most would accept nonwritten (oral) permission or general notification if obtaining written permission would make the research too difficult to conduct (range, 70.2% to 82.7%). Most perceived additional risk from each scenario (range, 64.0% to 81.6%). Limitation:Use of hypothetical scenarios and a nonprobability sample that was not fully representative of the U.S. population. Conclusion:Most respondents preferred to be asked for permission to participate in observational and randomized research evaluating usual medical practices, but they are willing to accept less elaborate approaches than written consent if research would otherwise be impracticable. These attitudes are not aligned with proposed regulatory guidance. Primary Funding Source:National Center for Advancing Translational Sciences at the National Institutes of Health.
Topics: informed consent, attitude, cross-sectional studies, medical records review
In this issue, Cho and colleagues surveyed adults about research on medical ethics and found that most respondents were willing to participate in such research but preferred to be asked for permission first. The editorialist addresses this sensitive topic by emphasizing that research participants should have a voice in shaping the current regulatory system for clinical research.
Topics: ethics, informed consent, therapeutics, voice, clinical research, ethics, research, fear
Reviews | 
Shelley Selph, MD, MPH; Tracy Dana, MLS; Ian Blazina, MPH; Christina Bougatsos, MPH; Hetal Patel, MD; and Roger Chou, MD
Background:Screening for type 2 diabetes mellitus could lead to earlier identification and treatment of asymptomatic diabetes, impaired fasting glucose (IFG), or impaired glucose tolerance (IGT), potentially resulting in improved outcomes. Purpose:To update the 2008 U.S. Preventive Services Task Force review on diabetes screening in adults. Data Sources:Cochrane databases and MEDLINE (2007 through October 2014) and relevant studies from previous Task Force reviews. Study Selection: Randomized, controlled trials; controlled, observational studies; and systematic reviews. Data Extraction:Data were abstracted by 1 investigator and checked by a second; 2 investigators independently assessed study quality. Data Synthesis:In 2 trials, screening for diabetes was associated with no 10-year mortality benefit versus no screening (hazard ratio, 1.06 [95% CI, 0.90 to 1.25]). Sixteen trials consistently found that treatment of IFG or IGT was associated with delayed progression to diabetes. Most trials of treatment of IFG or IGT found no effects on all-cause or cardiovascular mortality, although lifestyle modification was associated with decreased risk for both outcomes after 23 years in 1 trial. For screen-detected diabetes, 1 trial found no effect of an intensive multifactorial intervention on risk for all-cause or cardiovascular mortality versus standard control. In diabetes that was not specifically screen-detected, 9 systematic reviews found that intensive glucose control did not reduce risk for all-cause or cardiovascular mortality and results for intensive blood pressure control were inconsistent. Limitation:The review was restricted to English-language articles, and few studies were conducted in screen-detected populations. Conclusion:Screening for diabetes did not improve mortality rates after 10 years of follow-up. More evidence is needed to determine the effectiveness of treatments for screen-detected diabetes. Treatment of IFG or IGT was associated with delayed progression to diabetes. Primary Funding Source:Agency for Healthcare Research and Quality.
Topics: diabetes mellitus, diabetes mellitus, type 2, impaired fasting glucose
In this issue, Selph and colleagues review evidence for screening for type 2 diabetes and prediabetes. The editorialists discuss the review and its implications for clinical practice.
Topics: hyperglycemia, diabetes prevention, diabetes mellitus, type 2, prediabetes
Ideas and Opinions | 
Andrew J. Vickers, DPhil; and David M. Kent, MD, CM, MSc
This commentary discusses the paradoxical finding that most patients are at below-average risk and can expect to experience less-than-average benefits from a treatment. This “Lake Wobegon effect,” the authors argue, can result in too many patients being screened, diagnosed, and treated.
Topics: therapeutics, lung cancer, overtreatment, smoking
Ideas and Opinions | 
Frank H. Bosch, MD, PhD; and David A. Fleming, MD, MA
In hospitals, physicians perform cardiopulmonary resuscitation (CPR) in hospitals repeatedly and reflexively. Too often CPR occurs regardless of prognosis, without knowing whether the patient desires CPR, and knowing that we may do harm. In this commentary, leaders of the European Federation of Internal Medicine and American College of Physicians remind physicians of the importance of discussing patient preferences for CPR and individual patient prognosis after CPR with hospitalized patients.
Topics: cardiopulmonary resuscitation
New guidelines from the American Gastroenterological Association on the management of incidental pancreatic cysts recommend less aggressive evaluation than previous recommendations from other groups. The guidelines are needed because the rapid growth in the number of sensitive imaging studies has led to a marked increase in incidental pancreatic cysts. This commentary discusses lessons extending beyond pancreatic cysts about how physicians should consider diagnostic testing and what types of recommendations merit their attention.
Topics: pancreas, incidental findings
Ideas and Opinions | 
Giulio R. Romeo, MD; and Martin J. Abrahamson, MD
Each year, the American Diabetes Association's Standards of Medical Care in Diabetes provide comprehensive clinical practice recommendations for diabetes care, based on the latest available evidence. This commentary highlights 3 topics in the Standards of relevance to nonendocrinologists who care for patients with diabetes: ethnic differences in diabetes risk with different body mass indices, blood pressure targets, and individualization of diabetes treatment goals.
Topics: diabetes mellitus, patient-centered care, diabetes mellitus, type 2
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