Bernadette Zakher

Screening for Lung Cancer With Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

BACKGROUND Lung cancer is the leading cause of cancer-related death in the United States. Because early-stage lung cancer is associated with lower mortality than late-stage disease, early detection and treatment may be beneficial. PURPOSE To update the 2004 review of screening for lung cancer for the U.S. Preventive Services Task Force, focusing on screening with low-dose computed tomography (LDCT). DATA SOURCES MEDLINE (2000 to 31 May 2013), the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2012), Scopus, and reference lists. STUDY SELECTION English-language randomized, controlled trials or cohort studies that evaluated LDCT screening for lung cancer. DATA EXTRACTION One reviewer extracted study data about participants, design, analysis, follow-up, and results, and a second reviewer checked extractions. Two reviewers rated study quality using established criteria. DATA SYNTHESIS Four trials reported results of LDCT screening among patients with smoking exposure. One large good-quality trial reported that screening was associated with significant reductions in lung cancer (20%) and all-cause (6.7%) mortality. Three small European trials showed no benefit of screening. Harms included radiation exposure, overdiagnosis, and a high rate of false-positive findings that typically were resolved with further imaging. Smoking cessation was not affected. Incidental findings were common. LIMITATIONS Three trials were underpowered and of insufficient duration to evaluate screening effectiveness. Overdiagnosis, an important harm of screening, is of uncertain magnitude. No studies reported results in women or minority populations. CONCLUSION Strong evidence shows that LDCT screening can reduce lung cancer and all-cause mortality. The harms associated with screening must be balanced with the benefits. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Risk Factors for Breast Cancer for Women Aged 40 to 49 Years: A Systematic Review and Meta-analysis

BACKGROUND Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions. PURPOSE To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor. DATA SOURCES MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium. STUDY SELECTION English-language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor. DATA EXTRACTION Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means. DATA SYNTHESIS Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk. LIMITATIONS Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered. CONCLUSION Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening. PRIMARY FUNDING SOURCE National Cancer Institute.

Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

The U.S. Preventive Services Task Force (USPSTF) recommended in 2005 that women whose family histories are associated with increased risks for clinically significant, or deleterious, mutations in the BRCA1 or BRCA2 gene be referred for genetic counseling and evaluation for mutation testing (1). This recommendation was intended for primary prevention of cancer and applies to women without previous diagnoses of breast or ovarian cancer. Deleterious mutations in the BRCA1 and BRCA2 genes are associated with increased risks for breast, ovarian, fallopian tube, and peritoneal cancer in women and breast cancer in men (2). They are also, to a lesser degree, associated with pancreatic and early-onset prostate cancer, and BRCA2 mutations are associated with melanoma. Mutations in BRCA genes cluster in families exhibiting an autosomal dominant pattern of transmission and account for 5% to 10% of cases of breast cancer overall (3, 4). Specific BRCA mutations, known as founder mutations, occur among certain ethnic groups, including Ashkenazi Jewish (57), black (8), and Hispanic persons (9, 10), and in identified families (1115). Other genes are associated with hereditary susceptibility to breast and ovarian cancer but are not commonly tested, such as PTEN (the Cowden syndrome) and TP53 (the LiFraumeni syndrome) (2, 16). Genetic risk assessment and testing involve determining individual risk for BRCA mutations, followed by selective testing of high-risk persons. Characteristics associated with an increased likelihood ofBRCA mutations (1720) include breast and ovarian cancer in relatives and young age at onset. These and other individual and family characteristics can be used to assess personal mutation risk and the need for referral for additional evaluation. Genetic counseling is the process of identifying and counseling persons at risk for familial or inherited cancer and is recommended before testing (21, 22). Guidelines recommend testing for mutations only when an individual has a personal or family history of cancer suggestive of inherited cancer susceptibility and the results can be adequately interpreted and will aid in management (23). The type of mutation analysis that is required depends on family history. Persons without links to families or groups with known mutations (510, 1214) generally have direct DNA sequencing. For appropriate candidates, interventions to reduce cancer risk include earlier, more frequent, or intensive cancer screening; risk-reducing medications; and risk-reducing surgery, including bilateral mastectomy and salpingo-oophorectomy. This systematic review is an update of a prior review (1, 24, 25) for the USPSTF on the effectiveness and adverse effects of risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. Its purpose is to evaluate and summarize research addressing specific key questions important to the USPSTF as it considers new recommendations for primary care practice. Methods This research is part of a comprehensive systematic review that includes an additional analysis of studies of the prevalence and penetrance of BRCA mutations that is not included in this manuscript (26). We followed a standard protocol consistent with the Agency for Healthcare Research and Quality (AHRQ) methods for systematic reviews (27). On the basis of evidence gaps identified from a prior review (24, 25), the USPSTF and AHRQ determined the key questions for this update by using the methods of the USPSTF (28). Investigators created an analytic framework incorporating the key questions and outlining the patient populations, interventions, outcomes, and potential adverse effects (Appendix Figure 1). A work plan was externally reviewed and modified. Appendix Figure 1. Analytic framework and key questions. KQ = key question; MRI = magnetic resonance imaging. * Clinically significant mutations of the BRCA1 or BRCA2 gene or related syndromes. Testing may be done on the unaffected woman, the relative with cancer, or the relative with the highest risk, as appropriate. No known mutation in relatives and none detected in the patient. Known mutation in relatives but none detected in the patient. Interventions include increased early detection through intensive screening (e.g., earlier and more frequent mammography and breast MRI), risk-reducing medications (tamoxifen and raloxifene), and risk-reducing surgery (mastectomy and salpingo-oophorectomy). The target population includes women without cancer or known BRCA mutations who are seen in clinical settings applicable to U.S. primary care practice, although the ideal candidate for mutation testing could be a male or female relative withcancer. The conditions of interest are mutation carrier status and BRCA-related cancer (predominantly breast, ovarian, fallopian tube, and peritoneal). Although other types of cancer are also considered during familial risk assessment, studies with these cancer outcomes are outside the scope of this review. Data Sources We searched MEDLINE from 2004 to 30 July 2013, the Cochrane Central Register of Controlled Trials and Cochrane Databaseof Systematic Reviews from 2004 through the second quarter of 2013, and Health Technology Assessment during the fourth quarter of 2012 for relevant English-language studies, systematic reviews, and meta-analyses. We manually reviewed reference lists of articles and reviewed citations of key studies by using Scopus. Study Selection Research published in 2004 or later and done in the United States or in populations that receive services and interventions applicable to medical practice in the United States was reviewed. Randomized, controlled trials (RCTs); systematic reviews; prospective and retrospective cohort studies; casecontrol studies; and diagnostic accuracy evaluations were included if they addressed the accuracy of risk assessment methods, outcomes of genetic counseling and testing, and the effectiveness of interventions to reduce BRCA-related cancer and mortality among mutation carriers. Risk assessment methods were included if they were designed to guide referrals to genetic counselors or other genetic specialists and could be used by nonspecialists in genetics in clinical settings (that is, methods that were brief and nontechnical and did not require special training to administer or interpret). Evaluation of comprehensive models used in the practice of genetic counseling was outside the scope of this review, which focuses on primary care practice. Interventions included intensive screening, risk-reducing medications, and risk-reducing surgery. Only risk-reducing medications approved by the U.S. Food and Drug Administration (that is, tamoxifen and raloxifene) were considered, consistent with the scope of the USPSTF. Studies of any design were included if they described potential adverse effects, including inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; false reassurance; incomplete testing; misinterpretation of results; anxiety; cancer-related worry; immediate and long-term harms associated with interventions; and ethical, legal, and social implications. For adverse effects of interventions, studies were included that enrolled women at high risk for BRCA-related cancer regardless of their mutation status. After an initial review of abstracts, we reviewed full-text articles by using additional inclusion criteria. Studies from the prior review that met inclusion criteria for the update were included to build on previous relevant research. Appendix Figure 2 shows the results of the search and selection process. Appendix Figure 2. Summary of evidence search and selection. * Identified from reference lists, hand-searching, suggestions from experts, and other methods. Results are provided in an additional publication (26). Studies that provided data and contributed to the body of evidence were considered to be included. Studies may contribute data to >1 key question. This number includes studies from the prior review as well as studies published since 2004. Data Abstraction and Quality Assessment An investigator abstracted data about the study design and setting; participant characteristics; procedures for data collection; number of participants enrolled and lost to follow-up; methods of exposure and outcome ascertainment; analytic methods, including adjustment for confounders; and outcomes. A second investigator confirmed the accuracy of key data. Two investigators used predefined criteria for RCTs; systematic reviews; and cohort, casecontrol, and diagnostic accuracy studies developed by the USPSTF (28, 29) to rate the quality of studies (good, fair, or poor) and resolved discrepancies by consensus. Quality could not be assessed for many studies with designs that did not have predefined criteria, such as descriptive, cross-sectional, and prepost studies and case series. The applicability of studies was determined using the population, intervention, comparator, outcomes, timing of outcomes measurement, and setting format adapted to this topic (30). Data Synthesis and Analysis Because of heterogeneity across studies, results were not combined in a quantitative meta-analysis. We assessed the aggregate quality of the body of evidence (good, fair, or poor) by using methods that the USPSTF developed on the basis of the number, quality, and size of studies and consistency of results between studies (28). Studies were considered consistent if outcomes were generally in the same direction of effect and ranges of effect sizes were narrow. Role of the Funding Source This research was funded by the AHRQ. Investigators worked with AHRQ staff and USPSTF members to define the scope, analytic framework, and key questions; resolve issues arising during the project; and review the final report to ensure that it met basic methodological standards for systematic reviews. The draft report was reviewed by content experts, USPSTF members, AHR

Screening for Vitamin D Deficiency: A Systematic Review for the U.S. Preventive Services Task Force

Vitamin D is obtained through food consumption and synthesis in the skin after ultraviolet (UV) B exposure (1). Researchers have reported associations between low 25-hydroxyvitamin D [25-(OH)D] levels and risk for fractures (26), falls (7, 8), cardiovascular disease (914), colorectal cancer (1320), diabetes (13, 14, 2129), depressed mood (13, 14, 30, 31), cognitive decline (13, 14), and death (13, 32). Vitamin D deficiency is determined by measuring total serum 25-(OH)D concentrations (33). Measuring 25-(OH)D levels is complicated by the presence of multiple assays (34); evidence of intermethod and interlaboratory variability in measurement (3543); and the lack of an internationally recognized, commutable vitamin D reference standard (44). Efforts to increase standardization are in progress (34, 44). There is no consensus on optimal 25-(OH)D concentrations. Although experts generally agree that levels lower than 50 nmol/L (20 ng/mL) are associated with bone health (36, 45), disagreement exists about whether optimal 25-(OH)D levels are higher than this threshold (Table 1). According to NHANES (National Health and Nutrition Examination Survey) data from 2001 to 2006, 33% of the U.S. population was at risk for 25-(OH)D levels below 50 nmol/L (20 ng/mL) (47) and 77% had 25-(OH)D levels below 75 nmol/L (30 ng/mL) (48). Risk factors for low vitamin D levels include darker skin pigmentation (33), low vitamin D intake (4951), little or no UVB exposure (49, 50, 5254), and obesity (4951, 55). Older age (4953), female sex (49, 51, 52), low physical activity (49, 50, 53), low education attainment (48), and low health status (51, 54) were factors also associated with vitamin D deficiency in some studies. Table 1. Summary of Current Opinions About Appropriate 25-(OH)D Level Cutoffs for Defining Vitamin D Deficiency and Associations Between These Cutoffs and Health Outcomes* Vitamin D deficiency is treated by increasing dietary intake of food fortified with vitamin D or oral vitamin D treatment. Two commonly available vitamin D treatments (vitamin D3 [cholecalciferol] and vitamin D2 [ergocalciferol]) are available in several forms (for example, tablet and gel capsule), dosages (for example, 200 to 500000 IU), and dosing regimens (for example, daily, weekly, monthly, or yearly) and can be given in combination with oral calcium (56, 57). Potential harms of vitamin D treatment include hypercalcemia, hyperphosphatemia, suppressed parathyroid hormone levels, and hypercalciuria (46, 58, 59). Although very high levels of vitamin D are associated with other potential harms, these events are rare with typical replacement doses (Table 1). Screening for vitamin D deficiency can identify persons with low levels who might benefit from treatment. This report reviews the current evidence on vitamin D screening in asymptomatic adults to help the U.S. Preventive Services Task Force (USPSTF) develop a recommendation statement. Although the USPSTF has not previously issued recommendations on screening for vitamin D deficiency, it has made recommendations on vitamin D supplementation to prevent adverse health outcomes (for example, falls, fractures, cancer, and cardiovascular disease) in populations not necessarily vitamin Ddeficient (that is, general populations who may or may not have been deficient) (6063). Methods Scope of the Review We developed a review protocol and analytic framework (Appendix Figure 1) that included the following key questions: Appendix Figure 1. Analytic framework. Numbers on figures indicate key questions. For a list of key questions, see the Methods section or Table 2. 1. Is there direct evidence that screening for vitamin D deficiency results in improved health outcomes? 1a. Are there differences in screening efficacy between patient subgroups? 2. What are the harms of screening (for example, risk for procedure, false positives, or false negatives)? 3. Does treatment of vitamin D deficiency using vitamin D lead to improved health outcomes? 3a. Are there differences in efficacy between patient subgroups? 4. What are the adverse effects of treatment of vitamin D deficiency using vitamin D? 4a. Are there differences in adverse effects between patient subgroups? Detailed methods and data for this review are contained in the full report, including search strategies, inclusion criteria, abstraction and quality rating tables, and contextual questions (46). We developed our protocol using a standardized process after gathering input from experts and the public. The analytic framework focuses on direct evidence that screening for vitamin D deficiency improves important health outcomes (for example, death, falls, fractures, functional status, or risk for cancer) versus not screening. Further, the framework details evidence that treatment in persons found to have vitamin D deficiency is associated with improved health outcomes, harms resulting from screening or subsequent treatment, and how effects of screening and treatment vary in subgroups defined by demographic and other factors (for example, body mass index, UV exposure, and institutionalized status). We did not review the accuracy of vitamin D testing because of the lack of an accepted reference standard and studies reporting diagnostic accuracy. For the purposes of this report, the term vitamin Ddeficient refers to populations in which at least 90% of persons have 25-(OH)D levels of 75 nmol/L (30 ng/mL) or less. For studies that did not restrict enrollment to persons with 25-(OH)D levels of 75 nmol/L (30 ng/mL), we used the mean 25-(OH)D level plus the SD multiplied by 1.282 to approximate the 90th percentile to determine whether this level was at or below the 75-nmol/L (30-ng/mL) threshold. Because of uncertainty about what 25-(OH)D level constitutes deficiency, we stratified studies according to whether at least 90% of persons had levels less than 50 nmol/L (<20 ng/mL in this report) or at least 90% had levels less than 75 nmol/L (30 ng/mL) with at least 10% greater than 50 nmol/L (20 ng/mL) (75 nmol/L [30 ng/mL] in this report). Data Sources and Searches A research librarian searched Ovid MEDLINE (1946 through the third week of August 2014), Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (through August 2014). We supplemented our electronic searches by reviewing reference lists of retrieved articles. Study Selection At least 2 reviewers independently evaluated each study to determine inclusion eligibility. For screening studies, we included randomized, controlled trials (RCTs) of screening for vitamin D deficiency versus no screening in healthy, asymptomatic adults (aged 18 years). For studies of the effectiveness of vitamin D treatment, we included RCTs of vitamin D treatment with or without calcium versus placebo or no treatment in vitamin Ddeficient persons that reported health outcomes after at least 8 weeks of treatment. Because the Womens Health Initiative (WHI) is the largest RCT about vitamin D (64), we included data from nested casecontrol studies of WHI participants with known 25-(OH)D status. We included English-language articles only and excluded studies published only as abstracts. We included studies conducted in the United States, Canada, United Kingdom, and other geographic settings generalizable to the United States. We excluded studies that specifically targeted populations with symptoms or conditions associated with vitamin D deficiency (for example, osteoporosis, history of nontraumatic fractures, or history of falls) or with medical conditions that increase a persons risk for deficiency (such as liver, kidney, or malabsorptive disease) because screening and treatment of vitamin D deficiency could be a component of medical management in these conditions. The summary of evidence search and selection is shown in Appendix Figure 2. Appendix Figure 2. Summary of evidence search and selection. 25-(OH)D = 25-hydroxyvitamin D. * Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Identified from reference lists or by hand-searching or suggested by experts. Studies that provided data and contributed to the body of evidence were considered included. Studies may have provided data for more than 1 key question or published article; 27 unique studies were included, and a total of 35 articles were included. Data Abstraction and Quality Rating One investigator abstracted details about the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results. A second investigator reviewed data for accuracy. Two investigators independently applied USPSTF criteria (65) to rate the quality of each study as good, fair, or poor. We resolved discrepancies through a consensus process. We excluded from data synthesis studies rated as poor quality. Those studies had 1 or more fatal flaws, including inadequate randomization or lack of intervention fidelity combined with postrandomization exclusions, high rates of withdrawals, and unclear randomization. Data Synthesis and Analysis We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) using methods developed by the USPSTF on the basis of the number, quality, and size of studies; consistency of results; and directness of evidence (65). We conducted meta-analyses to calculate risk ratios (RRs) using the DerSimonianLaird random-effects model (Review Manager, version 5.2; Cochrane Collaboration). Analyses were based on total follow-up (including time after discontinuation of vitamin D treatment). For falls per person, we calculated incidence rate ratios and assumed equal mean length of follow-up across treatment groups if these data were not reported. For analyses with between-study heterogeneity, we conducted sensitivity analyses using profile likelihood random-effects models (66). Rate ratio analysis and analyses using the profil

Preventing Dental Caries in Children <5 Years: Systematic Review Updating USPSTF Recommendation

BACKGROUND AND OBJECTIVE: Screening and preventive interventions by primary care providers could improve outcomes related to early childhood caries. The objective of this study was to update the 2004 US Preventive Services Task Force systematic review on prevention of caries in children younger than 5 years of age. METHODS: Searching Medline and the Cochrane Library (through March 2013) and reference lists, we included trials and controlled observational studies on the effectiveness and harms of screening and treatments. One author extracted study characteristics and results, which were checked for accuracy by a second author. Two authors independently assessed study quality. RESULTS: No study evaluated effects of screening by primary care providers on clinical outcomes. One good-quality cohort study found pediatrician examination associated with a sensitivity of 0.76 for identifying a child with cavities. No new trials evaluated oral fluoride supplementation. Three new randomized trials were consistent with previous studies in finding fluoride varnish more effective than no varnish (reduction in caries increment 18% to 59%). Three trials of xylitol were inconclusive regarding effects on caries. New observational studies were consistent with previous evidence showing an association between early childhood fluoride use and enamel fluorosis. Evidence on the accuracy of risk prediction instruments in primary care settings is not available. CONCLUSIONS: There is no direct evidence that screening by primary care clinicians reduces early childhood caries. Evidence previously reviewed by the US Preventive Services Task Force found oral fluoride supplementation effective at reducing caries incidence, and new evidence supports the effectiveness of fluoride varnish in higher-risk children.

Screening for HIV: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

BACKGROUND A 2005 U.S. Preventive Services Task Force (USPSTF) review found good evidence that HIV screening is accurate and that antiretroviral therapy (ART) for immunologically advanced disease is associated with substantial clinical benefits, but insufficient evidence to determine the effects on transmission or in less immunologically advanced disease. PURPOSE To update the 2005 USPSTF review on benefits and harms of HIV screening in adolescents and adults, focusing on research gaps identified in the prior review. DATA SOURCES MEDLINE (2004 to June 2012) and the Cochrane Library (through the second quarter of 2012). STUDY SELECTION Randomized trials and observational studies that compared HIV screening strategies and reported clinical outcomes, evaluated the effects of starting ART at different CD4 cell count thresholds and long-term harms, or reported the effects of interventions on transmission risk. DATA EXTRACTION 2 authors abstracted and checked study details and quality using predefined criteria. DATA SYNTHESIS No study directly evaluated the effects on clinical outcomes of screening versus no screening for HIV infection. A randomized trial and a subgroup analysis from a randomized trial found that ART initiation at CD4 counts less than 0.250 × 109 cells/L was associated with a higher risk for death or AIDS-defining events than initiation at CD4 counts greater than 0.350 × 109 cells/L (hazard ratios, 1.7 [95% CI, 1.1 to 2.5] and 5.3 [CI, 1.3 to 9.6]). Large, fair-quality cohort studies also consistently found that ART initiation at CD4 counts of 0.350 to 0.500 × 109 cells/L was associated with lower risk for death or AIDS-defining events than delayed initiation. New evidence from good-quality cohorts with longer-term follow-up confirms a previously observed small increased risk for cardiovascular events associated with certain antiretrovirals. Strong evidence from 1 good-quality randomized trial and 7 observational studies found that ART was associated with a 10- to 20-fold reduction in risk for sexual transmission of HIV. LIMITATIONS Only English-language articles were included. Observational studies were included. Studies done in resource-poor or high-prevalence settings were included but might have limited applicability to general screening in the United States. CONCLUSION Previous studies have shown that HIV screening is accurate, targeted screening misses a substantial proportion of cases, and treatments are effective in patients with advanced immunodeficiency. New evidence indicates that ART reduces risk for AIDS-defining events and death in persons with less advanced immunodeficiency and reduces sexual transmission of HIV. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Hepatocellular carcinoma (HCC) is the most common primary malignant neoplasm of the liver, usually developing in persons with chronic liver disease. Worldwide, it is the fifth most common type of cancer and the third most common cause of death from cancer (1). There were 25000 deaths attributed to liver and intrahepatic bile duct cancer in the United States in 2011 (2). Common causes of HCC are hepatitis C virus infection, hepatitis B virus infection, and alcohol abuse, although a substantial proportion of cases have no identifiable cause (35). Imaging modalities for HCC include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Although CT and MRI provide higher-resolution images than ultrasonography, they are also more costly and, in the case of CT, are associated with radiation exposure (5). Because HCC is typically a hypervascular lesion, CT and MRI are performed with arterial-enhancing contrast agents. Microbubble-enhanced ultrasonography can also be performed, although agents are not yet approved by the U.S. Food and Drug Administration for this purpose, and microbubbles are present in the liver for only a limited duration (6). Other technical, patient, and tumor factors may also affect test performance (712). This article reviews the test performance of ultrasonography, MRI, and CT for detection of HCC and for evaluation of focal liver lesions. This was conducted as part of a larger review commissioned by the Agency for Healthcare Research and Quality (AHRQ) on HCC imaging (13). Supplement. Original Version (PDF) Methods Scope of the Review The protocol was developed by using a standardized process with input from experts and the public and was registered in the PROSPERO database (CRD42014007016) (14). The review protocol included key questions on the comparative test performance of imaging for detection of HCC and for evaluation of focal liver lesions. Detailed methods and data for the review, including search strategies, inclusion criteria, and abstraction and quality ratings tables, are available in the full report, which also includes further key questions, full sensitivity and subgroup analyses, and an additional imaging modality (positron emission tomography) (13). Data Sources and Searches A research librarian searched multiple electronic databases, including MEDLINE (1998 to December 2013 for the full report; the update search for the review in this article was performed in December 2014), the Cochrane Library, and Scopus. Additional studies were identified by reviewing reference lists and from peer review suggestions. Study Selection Two investigators independently evaluated each study at the title/abstract and full-text article stages to determine inclusion eligibility (Appendix Table 1). We included studies on the test performance of ultrasonography, CT, or MRI against a reference standard for detection of HCC in surveillance or nonsurveillance settings (for example, imaging performed in patients undergoing treatment for liver disease or in whom HCC was previously diagnosed) or for further evaluation of focal liver lesions. Reference standards were histopathologic examination based on explanted liver or nonexplant histologic specimens, imaging plus clinical follow-up (for example, lesion growth), or a combination of these. Appendix Table 1. Inclusion and Exclusion Criteria We selected studies of ultrasonography (with or without contrast) and contrast-enhanced CT and MRI that met minimum technical criteria (non-multidetector or multidetector spiral CT, or 1.5- or 3.0-T MRI) (7). We excluded studies published before 1998 and those in which imaging began before 1995, unless the imaging methods met minimum technical criteria; studies of MRI with contrast agents no longer commercially produced (for example, superparamagnetic iron oxide [ferumoxides or ferucarbotran] or mangafodipir); and studies of CT arterial portography, CT hepatic angiography, and intraoperative ultrasonography. We included studies of ultrasonography microbubble contrast agents because they are commercially available and commonly used outside the United States, and efforts to obtain approval from the U.S. Food and Drug Administration are ongoing (1517). We excluded studies of diagnostic accuracy for non-HCC malignant lesions, including liver metastases. We included studies that reported results for HCC and cholangiocarcinoma together if cholangiocarcinoma lesions comprised less than 10% of the total. Studies on the accuracy of imaging for distinguishing HCC from a specific type of liver lesion (such as hemangioma or pseudolesion) and on the accuracy of imaging tests used in combination are addressed in the full report (13). We excluded studies published only as conference abstracts and included only English-language articles. The literature flow diagram is shown in Appendix Figure 1. Appendix Figure 1. Summary of evidence search and selection. * Studies of positron emission tomography; effects on clinical decisions, clinical outcomes, or staging; and accuracy for distinguishing hepatocellular carcinoma lesions from another specific type of liver lesion are addressed in the full report (13). Data Abstraction and Quality Rating One investigator abstracted details on the study design, dates of imaging and publication, patient population, country, sample size, imaging method and associated technical factors (Appendix Table 2), and results. Two investigators independently applied the approach recommended in the AHRQ Methods Guide for Medical Test Reviews to assess risk of bias as high, moderate, or low (18, 19). Appendix Table 2. Technical Factors Abstracted, by Imaging Modality Data Synthesis We conducted meta-analysis with a bivariate logistic mixed random-effects model that incorporated the correlation between sensitivity and specificity, using SAS software, version 9.3 (SAS Institute) (20). We assumed bivariate normal distributions for sensitivity and specificity. Statistical heterogeneity was measured with the random-effect variance (2). We calculated positive and negative likelihood ratios by using the summarized sensitivity and specificity (21, 22). We analyzed data separately for each imaging modality; ultrasonography with and without contrast were also analyzed separately. We also separately analyzed studies in which imaging was performed for detection of HCC and for evaluation of focal liver lesions; studies on HCC detection were further stratified by setting (surveillance or nonsurveillance). We separately analyzed test performance by using patients with HCC or by using HCC lesions (one patient can have multiple lesions) as the unit of analysis. Other sensitivity and subgroup analyses were conducted on the reference standard, factors related to risk of bias, country, technical factors (Appendix Table 2), tumor factors (such as HCC lesion size or degree of tumor differentiation), and patient characteristics (for example, severity of underlying liver disease, underlying cause of liver disease, and body mass index). We performed separate analyses on the subset of studies that directly compared 2 or more imaging modalities or techniques in the same population against a common reference standard (23). We used the same bivariate logistic mixed-effects model as described above, with an added indicator variable for imaging modalities. We also performed meta-analyses for within-study comparisons on lesion size, degree of tumor differentiation, and (when data were available) technical factors. We graded the strength of each body of evidence as high, moderate, low, or insufficient on the basis of the aggregate risk of bias, consistency, precision, and directness (24). Role of the Funding Source This research was funded by the AHRQ Effective Health Care Program. Investigators worked with AHRQ staff to develop and refine the review protocol. The AHRQ staff had no role in conducting the review, and the investigators are solely responsible for the content of the manuscript and the decision to submit for publication. Results Of the 5202 citations identified at the title and abstract level, 890 articles seemed to meet inclusion criteria and were selected for further full-text review. After full-text review, 241 studies (Appendix Table 3) met inclusion criteria for the key questions and imaging modalities addressed in this review (Appendix Figure 1). Appendix Table 3. References to Articles That Met the Inclusion Criteria Appendix Table 3Continued. Appendix Table 3Continued. Sixty-eight studies evaluated ultrasonography (Appendix Table 3), 131 evaluated CT (25153), and 125 evaluated MRI (Appendix Table 3). Almost all studies reported sensitivity, but specificity was available in only 139 studies. We rated 5 studies as having low risk of bias (56, 99, 128, 132, 154), 199 as having moderate risk of bias, and 89 as having high risk of bias (13). One hundred twenty-five studies avoided use of a casecontrol design, 160 used blinded design, and 75 were prospective. More studies were conducted in Asia (190 studies) than in Australia, Canada, the United States, or Europe (95 studies in total for these regions). In 166 studies, imaging began in or after 2003 (13). Twenty-eight studies evaluated CT using methods that met minimum technical specifications (8-row multidetector CT; contrast rate 3 mL/s; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm), and 67 studies evaluated MRI using methods that met minimum technical specifications (1.5- or 3.0-T MRI; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm). Seventy-three MRI studies evaluated use of hepatic-specific contrast (for example, gadoxetic acid or gadobenate). Forty-seven ultrasonography studies evaluated use of

The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms: A Systematic Review

The use of medicinal cannabis has become increasingly accepted in the United States and globally (1, 2). Eight states and the District of Columbia have legalized cannabis for recreational purposes, and 28 states and the District of Columbia have legalized it for medical purposes (3). Between 45% and 80% of persons who seek medical cannabis do so for pain management (4, 5). Among patients who are prescribed long-term opioid therapy for pain, up to 39% are also using cannabis (6, 7). Physicians will increasingly need to engage in evidence-based discussions with their patients about the potential benefits and harms of cannabis use. However, little comprehensive and critically appraised information exists about the benefits and harms of using cannabis to treat chronic pain. The objectives of this systematic review were to assess the efficacy of cannabis for treating chronic pain and to provide a broad overview of the short- and long-term physical and mental health effects of cannabis use in chronic pain and general patient populations. Methods Topic Development This article is part of a larger report commissioned by the Veterans Health Administration (8). A protocol describing the review plan was posted to a publicly accessible Web site before the study began (9). Data Sources and Searches We searched MEDLINE, Embase, PubMed, PsycINFO, Evidence-Based Medicine Reviews (including Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, Health Technology Assessments, and Cochrane Central Register of Controlled Trials), and gray literature sources from database inception through February 2016. We updated this search specifically for new randomized controlled trials (RCTs) and systematic reviews in March 2017. We obtained additional articles from systematic reviews, reference lists, and expert recommendations. We also searched for ongoing, unpublished, or recently completed studies on ClinicalTrials.gov, the International Clinical Trials Registry Platform, the ISRCTN Registry, National Institutes of Health RePORTER, and the Agency for Healthcare Research and Quality Grants On-Line Database. Supplement 1 provides details on the search strategy, which we developed in consultation with a research librarian. Supplement. Online Supplement Study Selection We included English-language studies assessing the effect on nonpregnant adults of plant-based cannabis preparations or whole-plant extracts, such as nabiximols, a nonsynthetic pharmaceutical product with a standard composition and dose (oromucosal spray delivering tetrahydrocannabinol [THC], 2.7 mg, and cannabidiol, 2.5 mg). We did not include synthesized, pharmaceutically prepared cannabinoids, such as dronabinol or nabilone, because they are not available in dispensaries, and the efficacy of synthetic cannabinoid preparations for chronic pain was examined in 2 recent reviews (10, 11). We broadly defined plant-based cannabis preparations to include any preparation of the cannabis plant itself (for example, cannabis cigarettes and oils) or cannabis plant extracts to capture the variety of products available in U.S. dispensaries (12). To address the efficacy of cannabis for treating chronic pain, we included controlled clinical trials and cohort studies. This review focuses specifically on pain outcomes, although our larger report and search were designed to include other outcomes, such as sleep and quality of life (8). Because data about harms in the general population might be applicable to chronic pain populations, we examined harms broadly and reported whether the data were derived from studies of the general population or populations with chronic pain. To capture potential cannabis-related harms that may be of interest to clinicians and patients, but whose prevalence has not been well-characterized in larger-scale observational studies, we also included case series and descriptive studies of emerging harms. Supplement 2 provides the criteria we used for study selection. We searched for primary literature and systematic reviews; we dual-reviewed 5% of identified abstracts and all of the included full-text articles to ensure reliability. Disagreements were resolved by a third reviewer. Given the broad scope of this review, we summarized data from existing systematic reviews. We included only reviews that clearly reported their search strategy, reported inclusion and exclusion criteria, and appraised the internal validity of the included trials (13). We prioritized the most recent reviews and those with the broadest scope. In addition, we included individual studies that met inclusion criteria and either were published after the end search date of the included review or were not included in a prior systematic review. Data Extraction and Quality Assessment For all reports, 2 investigators abstracted details of study design, setting, patient population, intervention, and follow-up, as well as important co-interventions, health outcomes, health care use, and harms. Two reviewers independently assessed each trial (including those that were identified from a prior systematic review) as having low, high, or unclear risk of bias (ROB) for the pain outcome using a tool developed by the Cochrane Collaboration (14). Disagreements were resolved by consensus. To assess the ROB of observational studies for the pain outcome, we considered potential sources of bias most relevant to this evidence base and adapted existing assessment tools (15, 16) (Supplement 3). Data Synthesis and Analysis For the subgroup of neuropathic pain studies, we did a study-level meta-analysis of the proportion of patients experiencing clinically significant (30%) pain relief (Supplement 4), and we used the profile-likelihood random-effects model (17) to combine risk ratios. We assessed the magnitude of statistical heterogeneity among the studies using the standard Cochran chi-square test, the I 2 statistic (18). All analyses were done using Stata/IC, version 13.1 (StataCorp). Clinical heterogeneity, variation in outcomes reported, and the small number of trials precluded meta-analysis for other subgroups and outcomes, so we reported these qualitatively. After group discussion, we classified the overall strength of evidence for each outcome as high, moderate, low, or insufficient on the basis of the consistency, coherence, and applicability of the body of evidence as well as the internal validity of individual studies (19, 20). Role of the Funding Source The U.S. Department of Veterans Affairs Quality Enhancement Research Initiative supported the review but had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, and approval of the manuscript; or decision to submit the manuscript for publication. Results After reviewing 13674 titles and abstracts, we included 13 systematic reviews and 62 primary studies (Figure). Table 1 provides study-level details and the ROB rating for each of the chronic pain trials. Table 2 summarizes findings, including the ROB rating, by pain subgroup. Table 3 summarizes the harms in both pain and general populations. Supplement 5 provides additional study-level data from pain studies not included in prior reviews and from studies on general harms. Figure. Literature flow diagram. * Includes Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessments, and Cochrane Central Register of Controlled Trials. Table 1. Characteristics and Findings of RCTs on Cannabis Extracts for Treating Chronic Pain* Table 2. Summary of Evidence of the Benefits of Cannabis in Populations With Chronic Pain Table 3. Summary of Evidence for the Harms of Cannabis in Chronic Pain and General Adult Populations Effects of Cannabis in Treating Chronic Pain We identified 22 RCTs (2142) from 2 recently published systematic reviews (10, 11) and an additional 8 studies (5 RCTs [4347] and 3 cohort studies [4850]) that met our inclusion criteria and were not included in prior reviews. The primary methods of continuous pain assessment were a visual analogue scale from 0 to 100 mm and a numerical rating scale (NRS) from 0 to 10 (where 0 indicated no pain and 10 indicated the worst possible pain). Some of the studies identified the proportion of participants who had clinically significant improvements in pain intensity (defined as 30% reduction, or approximately 2 points on the NRS and 20 mm on the visual analogue scale). Neuropathic Pain Thirteen trials examined the effects of cannabis-based preparations on neuropathic pain (Table 1). Participants had central or peripheral neuropathic pain related to various health conditions. Of these studies, 11 were rated as having low ROB (24, 27, 28, 30, 31, 33, 36, 39, 40, 43, 47), 1 as having unclear ROB (26), and 1 as having high ROB (35). Overall, we found low-strength evidence that cannabis may alleviate neuropathic pain in some patients (Table 2). Studies generally did not find clinically significant between-group differences on continuous pain scales, but a higher proportion of intervention patients had clinically significant pain relief up to several months later. Across 9 studies, intervention patients were more likely to report at least 30% improvement in pain (risk ratio, 1.43 [95% CI, 1.16 to 1.88]; I 2= 38.6%; P= 0.111) (Supplement 4). Most studies were small, few reported outcomes beyond 2 to 3 weeks, and none reported long-term outcomes. In the largest RCT, 246 patients with peripheral neuropathic pain self-titrated nabiximols up to a maximum dosage of 24 sprays per day or received a placebo (27). Those who completed the study (79 in the nabiximols group and 94 in the placebo group) and responded positively to the intervention had a significant decrease in pain (odds ratio, 1.97 [CI, 1.05 to 3.70]). However, among all participants, including those who did not have an intervention response, the reductio

Screening for Hepatitis B Virus Infection in Adolescents and Adults: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

In 2008, an estimated 704000 persons in the United States were chronically infected with hepatitis B virus (HBV) (1). Potential long-term sequelae of chronic HBV infection include cirrhosis, hepatic decompensation, and hepatocellular carcinoma (2). In 2010, deaths associated with HBV infection were estimated at 0.5 per 100000 persons (3). In the United States, persons born in countries with a prevalence of HBV infection of 2% or greater account for 47% to 95% of chronically infected persons (47). Persons at high risk for HBV infection include household contacts or sexual partners of persons with HBV infection, men who have sex with men, injection drug users, and HIV-positive persons. The number of reported acute cases of HBV infection in the United States decreased from more than 20000 annually in the mid-1980s to 2890 in 2011 (the actual number of new cases is estimated at 6.5 times the number of reported cases) (3). Globally, incidence of HBV infection has markedly decreased, particularly among younger persons, after the implementation of universal vaccination programs (1, 8). Screening for HBV infection could identify chronically infected persons who might benefit from antiviral therapies, surveillance to diagnose hepatocellular carcinoma, or interventions to reduce behaviors associated with progression of liver disease (for example, alcohol use) or transmission and to identify persons without HBV immunity who could benefit from vaccination (9). However, in 2004, the U.S. Preventive Services Task Force (USPSTF) recommended against screening asymptomatic persons for HBV infection (D recommendation) on the basis of a lack of evidence that screening improves clinical outcomes and the low prevalence of HBV infection in the general population (10). Other groups recommend screening high-risk persons (7, 9). The purpose of this report is to review the current evidence on screening for HBV infection in asymptomatic adolescents and adults, excluding pregnant women. This report differs from the previous USPSTF review (11) by including additional key questions on the benefits and harms of antiviral treatment and the association between improvements in intermediate outcomes after antiviral therapy and subsequent clinical outcomes. Methods Scope of the Review We developed a review protocol and analytic framework (Appendix Figure 1) that included the following key questions. Appendix Figure 1. Analytic framework. HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; KQ = key question. * The full report (12) addresses this KQ. 1. What are the benefits of screening for HBV infection versus no screening in asymptomatic adolescents and adults on morbidity, mortality, and disease transmission? 2. What are the harms of screening for HBV infection? 3. How well do different screening strategies identify persons with HBV infection? 4. In persons without evidence of HBV immunity, how effective is HBV vaccination at improving clinical outcomes? 5. How effective is antiviral treatment at improving intermediate outcomes? 6. How effective is antiviral treatment at improving health outcomes? 7. What are the harms associated with antiviral treatment for HBV infection? 8. Are improvements in intermediate outcomes after antiviral therapy associated with improvements in health outcomes? The full report (12) contains detailed methods and data, including search strategies, inclusion criteria, abstraction and quality rating tables, an additional key question on the effects of behavior change counseling and education, and results related to biochemical and composite intermediate outcomes. The protocol was developed by using a standardized process with input from experts and the public. The analytic framework focuses on direct evidence that screening for HBV infection improves important health outcomes versus not screening and the chain of indirect evidence linking screening to improved health outcomes. Links in the chain of indirect evidence include the yield and performance of testing strategies for identifying persons with HBV infection and benefits and harms from subsequent treatments. We did not re-review the accuracy of HBV serologic testing, which the USPSTF previously determined to be accurate (sensitivity and specificity >98%) (13). We also did not evaluate prenatal screening, which the USPSTF is not currently addressing. Data Sources and Searches A research librarian searched MEDLINE (1946 through January 2014), the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and PsycINFO. We supplemented electronic searches by reviewing reference lists of retrieved articles. Study Selection At least 2 reviewers independently evaluated each study to determine inclusion eligibility. For screening, we included randomized trials and observational studies that compared different screening strategies in asymptomatic adults without known abnormal liver enzyme levels. We also reported clinical outcomes or the sensitivity and number needed to screen (NNS) to identify 1 HBV-infected person or provided the data to calculate these variables. For treatment, we included placebo-controlled trials of vaccination of adolescents and adults without known immunity to HBV and relevant systematic reviews. For antiviral therapy, we included trials of monotherapy with a medication approved by the U.S. Food and Drug Administration versus placebo or no treatment or first-line antiviral therapies (entecavir, tenofovir, or pegylated interferon-2a) (9) versus other approved therapies (adefovir, nonpegylated interferon, lamivudine, or telbivudine) that reported clinical outcomes (mortality, cirrhosis, hepatic decompensation, hepatocellular carcinoma, need for transplantation, or disease transmission), intermediate outcomes (histologic, virologic, or serologic), or harms (withdrawals due to adverse events, serious adverse events, or overall adverse events). We included trials of interferon-2a (not approved for HBV infection) that reported clinical outcomes because evidence for interferon-2b and pegylated interferon was limited. For the association between achieving an intermediate outcome after antiviral treatment and subsequent clinical outcomes, we included cohort studies that reported adjusted risk estimates. We included only English-language articles and excluded studies published only as abstracts. We excluded trials of persons who did not respond to prior antiviral therapy or those who had virologic relapse and did not evaluate drug resistance as an outcome. We excluded studies of patients co-infected with HIV or hepatitis C virus, transplant recipients, and patients receiving hemodialysis. We excluded systematic reviews of antiviral therapies unless we were unable to abstract the primary studies because they were in a foreign language. Appendix Figure 2 shows the summary of evidence search and selection. Appendix Figure 2. Summary of evidence search and selection. * Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Reference lists of relevant articles. Some studies are included for >1 key question. The full report (12) addresses this key question. Data Abstraction and Quality Rating One investigator abstracted details about the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results. A second investigator reviewed data for accuracy. Two investigators independently applied criteria developed by the USPSTF (14, 15) to rate the quality of each study as good, fair, or poor. Discrepancies were resolved through consensus. Data Synthesis and Analysis We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) on the basis of the number, quality, and size of studies; consistency of results; and directness of evidence (14, 15). For antiviral therapy and vaccination, we conducted meta-analyses to calculate relative risks using the DerSimonianLaird random-effects model (Review Manager, version 5.2, Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Primary analyses for antiviral therapy were based on total follow-up (including events after discontinuation of treatment), although we conducted sensitivity analyses of events during antiviral therapy. For harms, we analyzed events that occurred during antiviral therapy. For all analyses, we stratified results by antiviral drug. Statistical heterogeneity was assessed by using the I 2 statistic (16). We did additional analyses in which trials were stratified by study quality, duration of follow-up (shorter or longer than 1 year), hepatitis B e antigen (HBeAg) status, and inclusion of patients with cirrhosis. Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis. Staff from the AHRQ provided project oversight; reviewed the report to ensure that the analysis met methodological standards; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The investigators are solely responsible for the content and the decision to submit the manuscript for publication. Results No study compared clinical outcomes or harms in persons screened for HBV infection versus those not screened (the first 2 key questions). Yield of Risk-Based Screening Methods One fair-quality cross-sectional study (n= 6194) done in a French clinic for sexually transmitted infections found that targeted screening of persons born in countries with a prevalence of chronic HBV infection of 2% or greater, men, and unemployed persons identified 98% (48 of 49) of infections while testing approximately two

Screening for Gonorrhea and Chlamydia: A Systematic Review for the U.S. Preventive Services Task Force

In 2005, on the basis of epidemiologic studies of screening and studies of the diagnostic accuracy of screening tests (13), the U.S. Preventive Services Task Force (USPSTF) recommended screening for gonorrhea in all sexually active or pregnant women at increased risk for infection (4). It recommended against routine screening in low-risk men and nonpregnant women and found insufficient evidence to recommend for or against routine screening in high-risk men and low-risk pregnant women. In 2007, on the basis of studies of the effectiveness of screening, harms, and diagnostic accuracy of screening tests (13), the USPSTF recommended screening for chlamydia in all sexually active or pregnant women younger than 25 years and in older, high-risk women (5). It recommended against routine screening in low-risk women, regardless of pregnancy status, and found insufficient evidence to recommend for or against screening in men. Gonorrhea and chlamydia are the 2 most commonly reported sexually transmitted infections (STIs) in the United States (6). In 2012, totals of 334826 cases of gonorrhea and 1422976 cases of chlamydia were reported to the Centers for Disease Control and Prevention (6). However, the true incidence of gonorrhea and chlamydia is difficult to estimate because most infections are undetected. In women, gonococcal and chlamydial infections are most often asymptomatic but can cause cervicitis and complications of pelvic inflammatory disease (PID), ectopic pregnancy, infertility, and chronic pelvic pain (6, 7). In men, these infections can cause urethritis and epididymitis (6, 8). Most men with gonococcal urethritis are symptomatic, prompting timely treatment that prevents serious complications (9). However, gonococcal infections at extragenital sites, including the pharynx and rectum, and genital chlamydial infections are typically asymptomatic. Gonorrhea and chlamydia can also facilitate HIV transmission in both men and women (6, 10, 11). Infection with either gonorrhea or chlamydia in pregnant women can lead to adverse neonatal outcomes, including preterm birth and transmission of infection to the newborn. Chlamydial infection also causes neonatal ophthalmia and pneumonia in infants. Age is a strong predictor of risk for both gonorrhea and chlamydia, and infection rates are greatest among persons aged 15 to 24 years (6). Although rates are greater for women than men (108.7 cases of gonorrhea per 100000 women vs. 105.8 per 100000 men; 643.3 cases of chlamydia per 100000 women vs. 262.6 per 100000 men), rates have increased more rapidly among men in recent years (6). Other risk factors include having new or multiple sex partners or a partner with an STI, inconsistent condom use, and history of previous or coexisting STIs (1, 2). These risk factors are often used to define persons at increased risk in screening recommendations. Rates differ among population subgroups, and black and Hispanic persons generally have greater rates of infections compared with white persons (6, 12). Men who have sex with men who were tested in STD Surveillance Network clinics in 2012 had median prevalence rates of 16.4% for gonorrhea and 12.0% for chlamydia (6). This systematic review is an update of previous reviews for the USPSTF (13). It focuses on new studies of the effectiveness and adverse effects of gonorrhea and chlamydia screening in asymptomatic men and women, including pregnant women and adolescents, as well as the diagnostic accuracy of screening tests. Methods Methods are further described in a technical report (13). We followed a standard protocol consistent with the Agency for Healthcare Research and Quality (AHRQ) methods for systematic reviews (14). On the basis of evidence gaps identified from previous reviews (13), the USPSTF and AHRQ determined the key questions for this update (15). The investigators created analytic frameworks incorporating the key questions and outlining the patient populations, interventions, outcomes, and potential adverse effects (Supplements 1 and 2). A work plan was externally reviewed and modified but was not registered. Supplement 1. Analytic framework and key questions for screening men and nonpregnant women, including adolescents. Supplement 2. Analytic framework and key questions for screening pregnant women. The target populations were asymptomatic, sexually active men and women, including pregnant women and adolescents. The key questions focused on the effectiveness of screening compared with not screening in preventing adverse health outcomes, effectiveness of different screening strategies, diagnostic accuracy of screening tests, and potential harms of screening. Screening strategies included selective screening of high-risk groups, sampling from various anatomical sites, cotesting for concurrent STIs (including HIV), and using different screening intervals, among others. Outcomes included reduction of complications of infection and transmission or acquisition of disease, including gonorrhea, chlamydia, and HIV. For pregnant women, outcomes also included reduction in maternal complications and adverse pregnancy and infant outcomes. Harms of screening included labeling, anxiety, false-positive and false-negative test results, and other consequences of testing. The efficacy and harms of antibiotic treatments were well-established and were not further evaluated. Data Sources and Searches We searched Ovid MEDLINE (1 January 2004 to 13 June 2014), the Cochrane Central Register of Controlled Trials (May 2014), the Cochrane Database of Systematic Reviews (May 2014), the Health Technology Assessment Database (May 2014), the Database of Abstracts of Reviews of Effects (May 2014), and ClinicalTrials.gov (May 2014) and reviewed reference lists for additional citations (13). Search terms are provided in Supplement 3. Supplement 3. MEDLINE Search Strategies Study Selection Abstracts were selected for full-text review if they included asymptomatic, sexually active men and women, including pregnant women and adolescents; were relevant to a key question; and met additional prespecified inclusion criteria for each key question (13). Although this update was intended to evaluate studies published since the previous USPSTF reviews, the scope, key questions, and inclusion criteria differ across reviews, resulting in the inclusion of older studies that have not been previously reviewed. We included only English-language articles and excluded studies that were published as abstracts only or did not report original data. The selection of studies is summarized in a literature flow diagram Supplement 4. Two reviewers independently evaluated each study to determine inclusion eligibility. Supplement 4. Literature flow diagram. Only randomized, controlled trials (RCTs) and controlled observational studies were included to evaluate the effectiveness of screening, whereas uncontrolled observational studies were also included to determine adverse effects. Studies of screening strategies were included if they adequately described the study population and comparison groups, features of the screening program, and outcome measures. Inclusion criteria were less restrictive for effectiveness studies than diagnostic accuracy studies because the main comparison concerned outcomes related to the overall approach of screening compared with nonscreening rather than the characteristics of the individual tests. Studies of the accuracy of diagnostic tests were included if they evaluated screening tests in asymptomatic participants using technologies and methods that have been cleared by the U.S. Food and Drug Administration (FDA) and are available for clinical practice in the United States. These inclusion criteria reflect the scope of the USPSTF recommendations about technologies and medications. On the basis of these criteria, rectal, pharyngeal, and self-collected vaginal specimens obtained in nonclinical settings and point-of-care or in-house tests were excluded. Tests that were previously cleared and subsequently removed from the U.S. market (such as the ligase chain reaction test) were also excluded (16). Included studies used credible reference standards, adequately described the study population, defined positive test results, and reported performance characteristics of tests (such as sensitivity and specificity) or provided data to calculate them. Data Abstraction and Quality Rating A single investigator abstracted details about study design, patient population, comparison groups, setting, screening method, analysis, follow-up, and results. A second investigator reviewed data abstraction for accuracy. By using prespecified criteria for RCTs, cohort, and diagnostic accuracy studies developed by the USPSTF (14), 2 investigators independently rated the quality of studies (good, fair, or poor) and resolved discrepancies by consensus. Data Synthesis and Analysis Two independent reviewers assessed the internal validity (quality) of the body of evidence for the new studies for each key question using methods developed by the USPSTF, on the basis of the number, quality, and size of studies; consistency of results among studies; and directness of evidence (14, 15). Statistical meta-analysis was not done because of methodological limitations of the studies and heterogeneity in study designs, interventions, populations, and other factors. Studies included in previous reviews were reviewed for consistency with current results; however, lack of studies and differences in scope, key questions, and inclusion criteria limited aggregate synthesis with the updated evidence. Role of the Funding Source This research was funded by AHRQ under a contract to support the work of the USPSTF. The investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic frameworks, and key questions; resolve issues during the project; and finalize the report. AHRQ had no role in study selection, quality assessment, syn