Shelley Selph

Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Spine Fusion: A Systematic Review and Meta-analysis

BACKGROUND Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used as a bone graft substitute in spinal fusion, which unites (fuses) bones in the spine. The accuracy and completeness of journal publications of industry-sponsored trials on the effectiveness and harms of rhBMP-2 has been called into question. PURPOSE To independently assess the effectiveness and harms of rhBMP-2 in spinal fusion and reporting bias in industry-sponsored journal publications. DATA SOURCES Individual-patient data (IPD) from 17 industry-sponsored studies; related internal documents; and searches of MEDLINE (1996 to August 2012), other databases, and reference lists. STUDY SELECTION Randomized, controlled trials (RCTs) and cohort studies of rhBMP-2 versus any control and uncontrolled studies of harms. DATA EXTRACTION Effectiveness outcomes in IPD were recalculated using consistent definitions. Study characteristics and results were abstracted by 1 investigator and confirmed by another. Two investigators independently assessed quality using predefined criteria. DATA SYNTHESIS Thirteen RCTs and 31 cohort studies were included. For lumbar spine fusion, rhBMP-2 and iliac crest bone graft were similar in overall success, fusion, and other effectiveness measures and in risk for any adverse event, although rates were high across interventions (77% to 93% at 24 months from surgery). For anterior lumbar interbody fusion, rhBMP-2 was associated with nonsignificantly increased risk for retrograde ejaculation and urogenital problems. For anterior cervical spine fusion, rhBMP-2 was associated with increased risk for wound complications and dysphagia. At 24 months, the cancer risk was increased with rhBMP-2 (risk ratio, 3.45 [95% CI, 1.98 to 6.00]), but event rates were low and cancer was heterogeneous. Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting. LIMITATIONS Outcome assessment was not blinded, and ascertainment of harms in trials was poor. No trials were truly independent of industry sponsorship. CONCLUSION In spinal fusion, rhBMP-2 has no proven clinical advantage over bone graft and may be associated with important harms, making it difficult to identify clear indications for rhBMP-2. Earlier disclosure of all relevant data would have better informed clinicians and the public than the initial published trial reports did. PRIMARY FUNDING SOURCE Yale University and Medtronic.

Systematic Review of the Benefits and Risks of Metformin in Treating Obesity in Children Aged 18 Years and Younger

IMPORTANCE Childhood obesity is an important public health problem with increasing prevalence. Because treatment often has limited success, new approaches must be identified. OBJECTIVE To evaluate the effectiveness and safety of metformin for treating obesity in children aged 18 years and younger without a diagnosis of diabetes mellitus. EVIDENCE REVIEW We included randomized clinical trials identified through searches of MEDLINE, the Cochrane Library, and ClinicalTrials.gov. Our primary outcome measure was change in body mass index (BMI, calculated as weight in kilograms divided by height in meters squared). We assessed study quality, pooled data using a random-effects model, and performed subgroup and sensitivity analyses. FINDINGS Fourteen randomized clinical trials were eligible. For BMI, moderate-strength evidence indicated a reduction of -1.38 (95% CI, -1.93 to -0.82) from baseline compared with control at 6 months. A similar, if less dramatic, effect was observed in studies less than 6 months, but the pooled estimate from studies of 1 year of treatment was not statistically significant. Subgroup analyses indicated smaller, but significant, effects for those with baseline BMI below 35, those of Hispanic ethnicity, those with acanthosis nigricans, those who had tried and failed diet and exercise programs, and in studies with more girls or higher mean age (adolescents). Moderate-strength evidence indicated that with metformin, 26% reported a gastrointestinal event compared with 13% in control groups (relative risk, 2.05; 95% CI, 1.19-3.54), although there was no difference in discontinuations due to adverse events. No serious adverse events were reported. CONCLUSIONS AND RELEVANCE Metformin provides a statistically significant, but very modest reduction in BMI when combined with lifestyle interventions over the short term. A large trial is needed to determine the benefits to subgroups or impacts of confounders. In the context of other options for treating childhood obesity, metformin has not been shown to be clinically superior.

Screening for Type 2 Diabetes Mellitus: A Systematic Review for the U.S. Preventive Services Task Force

In the United States, approximately 21 million persons received diabetes diagnoses in 2010, and an estimated 8 million cases were undiagnosed; roughly 90% to 95% of them have type 2 diabetes mellitus (1, 2). Prevalence of diabetes among U.S. adults has increased, from approximately 5% in 1995 to 8% in 2010 (3). Diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and blindness; a major cause of heart disease and stroke; and the seventh-leading cause of death in the United States (1). Risk factors for diabetes include obesity, physical inactivity, smoking, and older age (1). Diabetes is more common among certain ethnic and racial minorities (1, 3). Type 2 diabetes is caused by insulin resistance and relative insulin deficiency, resulting in the inability to maintain normoglycemia. Diabetes typically develops slowly (4, 5), although microvascular disease, such as retinopathy and neuropathy, may be present at the time of diagnosis due to vascular damage during the subclinical phase (4, 6). Screening asymptomatic persons (those without signs or symptoms of hyperglycemia and no clinical sequelae) may lead to earlier identification and earlier or more-intensive treatments, potentially improving health outcomes (2). Strategies for screening include routine screening or targeted screening based on the presence of risk factors, such as obesity or hypertension. In 2008, the U.S. Preventive Services Task Force (USPSTF) recommended diabetes screening in asymptomatic adults with sustained blood pressure (BP) (treated or untreated) greater than 135/80 mm Hg (B recommendation). Although direct evidence on benefits and harms of screening was not available, the recommendation was based on the ability of screening to identify persons with diabetes and evidence that more-intensive BP treatment was associated with reduced risk for cardiovascular events, including cardiovascular mortality, in patients with diabetes and hypertension. The USPSTF found insufficient evidence to assess the balance of benefits and harms of screening in adults without elevated BP (I statement). It also found that lifestyle and drug interventions for impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), defined as a hemoglobin A1c level of 5.7% to 6.4% or a fasting blood glucose level between 5.55 and 6.94 mmol/L (100 and 125 mg/dL) (2), were associated with reduced risk for progression to diabetes (714). Other groups also recommend screening persons with risk factors (1520). This article updates previous USPSTF reviews (2123) on diabetes screening in nonpregnant adults. 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. DM = diabetes mellitus; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; KQ = key question; MI = myocardial infarction. 1. Is there direct evidence that screening for type 2 diabetes, IFG, or IGT among asymptomatic adults improves health outcomes? 2. What are the harms of screening for type 2 diabetes, IFG, or IGT? 3. Do interventions for screen-detected or early diabetes, IFG, or IGT provide an incremental benefit in health outcomes compared with no interventions or initiating interventions after clinical diagnosis? 4. What are the harms of interventions for screen-detected or early diabetes, IFG, or IGT? 5. Is there evidence that more-intensive glucose, BP, or lipid control interventions improve health outcomes in adults with type 2 diabetes, IFG, or IGT compared with traditional control? Is there evidence that aspirin use improves health outcomes in these populations compared with nonuse? 6. What are the harms of more-intensive interventions compared with traditional control in adults with type 2 diabetes, IFG, or IGT? 7. Do interventions for IFG or IGT delay or prevent the progression to type 2 diabetes? The full report (24), on which this article is based, provides detailed methods and data for the review, including search strategies, evidence tables, and quality ratings of individual studies (available at www.uspreventiveservicestaskforce.org). The full report includes an additional key question on whether the effects of screening or interventions for screen-detected or early diabetes, IFG, or IGT vary by subgroup; effects of treatments on microvascular outcomes; and evidence on effects of more- versus less-intensive lipid control and aspirin use (24). Data Sources and Searches A research librarian searched the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews and MEDLINE (2007 to October 2014). We supplemented electronic searches by reviewing previous USPSTF reports and reference lists of relevant articles. Study Selection At least 2 reviewers independently evaluated each study to determine inclusion eligibility using predefined inclusion and exclusion criteria (Appendix Figure 2). Because of the limited evidence on treatment of screen-detected diabetes (key question 5), we also included studies of treatment of early diabetes (defined as a pharmacologically untreated hemoglobin A1c level <8.5% or diabetes diagnosis in the past year) that was not specifically screen-detected. Appendix Figure 3 summarizes the selection of literature. Appendix Figure 2. Inclusion and exclusion criteria per KQ. BP = blood pressure; DM = diabetes mellitus; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; KQ = key question; MI = myocardial infarction. Appendix Figure 3. Summary of evidence search and selection. KQ = key question. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. Other sources include previous reports, reference lists of relevant articles, and systematic reviews. An additional 27 publications are included in the full report (23). Some studies have several publications and some are included for more than 1 KQ. 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 abstraction for accuracy. Two investigators independently applied criteria developed by the USPSTF (25) to rate the quality of each study as good, fair, or poor. Discrepancies were resolved through a consensus process. Data Synthesis and Analysis We conducted meta-analyses to calculate risk ratios (RRs) on effects of interventions with the DerSimonianLaird random-effects model using Stata, version 12 (StataCorp). Statistical heterogeneity was assessed using the I 2 statistic (26). When statistical heterogeneity was present, we performed sensitivity analyses using the profile likelihood method because the DerSimonianLaird model results in overly narrow 95% CIs (27). Two studies (2830) that used a 22 factorial design reported no interaction between treatments and were analyzed as a 2-group parallel group trial for the comparison of interest. When studies evaluated several lifestyle strategies, we combined the lifestyle groups. We included all studies in meta-analyses, regardless of event rates. For rare events (incidence <1%), we calculated the Peto odds ratio (31). We stratified results by drug class or lifestyle intervention and performed additional sensitivity analyses based on study quality and presence of outlier trials. 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, based on the quality of studies, precision of estimates, consistency of results, and directness of evidence (25). 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 and refine the scope, analytic framework, and key questions; resolve issues arising during the project; and finalize the report. The AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. The AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. It also performed a final review of the manuscript to ensure that the analysis met methodological standards. The investigators are solely responsible for the content and the decision to submit the manuscript for publication. Results Benefits of Screening Two randomized, controlled trials (ADDITION [Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen Detected Diabetes in Primary Care]Cambridge [Cambridge, United Kingdom] trial [n=19226] [32], rated good-quality, and a trial conducted in Ely, United Kingdom [n=4936] [33], rated fair-quality) evaluated effects of diabetes screening versus no screening on mortality (Appendix Table 1). The ongoing ADDITION trial includes sites in Cambridge, the Netherlands, and Denmark on intensive versus standard treatment of screen-detected diabetes; however, only the Cambridge site had a no-screening component (34). Mean age ranged from 51 to 58 years, 36% to 54% of participants were women, and follow-up was 10 years in both studies (32, 33). In ADDITION-Cambridge, persons at high risk for diabetes, based on known risk factors, were randomly assigned in clusters by clinic site to screening or no screening (32). The Ely study randomly enrolled participants (not selected based on high risk for diabetes) to screening or no screening from a single practice site (33). Seventy-eight percent of participants (11737 of 15089) invited to screening had screening in the ADDITION trial (32); 68% of participants in the Ely study were screened (33). Methodological shortcomings in the Ely study included unclear randomization and allocation concealment method

Behavioral Interventions and Counseling to Prevent Child Abuse and Neglect: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

BACKGROUND In 2004, the U.S. Preventive Services Task Force determined that evidence was insufficient to recommend behavioral interventions and counseling to prevent child abuse and neglect. PURPOSE To review new evidence on the effectiveness of behavioral interventions and counseling in health care settings for reducing child abuse and neglect and related health outcomes, as well as adverse effects of interventions. DATA SOURCES MEDLINE and PsycINFO (January 2002 to June 2012), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the second quarter of 2012), Scopus, and reference lists. STUDY SELECTION English-language trials of the effectiveness of behavioral interventions and counseling and studies of any design about adverse effects. DATA EXTRACTION Investigators extracted data about study populations, designs, and outcomes and rated study quality using established criteria. DATA SYNTHESIS Eleven fair-quality randomized trials of interventions and no studies of adverse effects met inclusion criteria. A trial of risk assessment and interventions for abuse and neglect in pediatric clinics for families with children aged 5 years or younger indicated reduced physical assault, Child Protective Services (CPS) reports, nonadherence to medical care, and immunization delay among screened children. Ten trials of early childhood home visitation reported reduced CPS reports, emergency department visits, hospitalizations, and self-reports of abuse and improved adherence to immunizations and well-child care, although results were inconsistent. LIMITATION Trials were limited by heterogeneity, low adherence, high loss to follow-up, and lack of standardized measures. CONCLUSION Risk assessment and behavioral interventions in pediatric clinics reduced abuse and neglect outcomes for young children. Early childhood home visitation also reduced abuse and neglect, but results were inconsistent. Additional research on interventions to prevent child abuse and neglect is needed. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Urinary biomarkers for diagnosis of bladder cancer: A systematic review and meta-analysis

Bladder cancer is the fourth most commonly diagnosed cancer in U.S. men and the 10th most commonly diagnosed cancer in U.S. women (1). Standard methods for diagnosis of bladder cancer involve cytologic evaluation of urine, imaging tests, and cystoscopy (2, 3). Because cystoscopy is uncomfortable and costly, alternative diagnostic methods have been sought. Urine-based biomarkers have been developed as potential alternatives or adjuncts to standard tests for the initial diagnosis of bladder cancer or identification of recurrent disease (4). Six urinary biomarkers have been approved by the U.S. Food and Drug Administration (FDA) for diagnosis or surveillance of bladder cancer: quantitative nuclear matrix protein 22 (NMP22) (Alere NMP22 [Alere]), qualitative NMP22 (BladderChek [Alere]), qualitative bladder tumor antigen (BTA) (BTA stat [Polymedco]), quantitative BTA (BTA TRAK [Polymedco]), fluorescence in situ hybridization (FISH) (UroVysion [Abbott Molecular]), and fluorescent immunohistochemistry (ImmunoCyt [Scimedx]). The qualitative NMP22 and BTA tests can be performed as point-of-care tests, and the others are performed in a laboratory. One additional test, Cxbladder (Pacific Edge Diagnostics USA), is a laboratory-developed test that does not require FDA approval. Other biomarkers have been developed but are not FDA-approved. The purpose of this study was to systematically review the evidence on the comparative accuracy of urinary biomarkers for diagnosis of bladder cancer. It was done as part of a larger review (5) on the evaluation and treatment of nonmuscle-invasive bladder cancer that was nominated to the Agency for Healthcare Research and Quality (AHRQ) by the American Urological Association for use in updating its guidelines. Methods Detailed methods and data for this review, including the analytic framework, key questions, search strategies, inclusion criteria, study data extraction, and quality ratings, are available in the full report (5). The protocol was developed using a standardized process (6) with input from experts and the public and is registered in the PROSPERO database (7). This article focuses on the accuracy of urinary biomarkers for initial diagnosis of bladder cancer or for diagnosis of recurrent disease, including any variance in diagnostic accuracy based on tumor characteristics, patient characteristics, or the nature of presenting signs or symptoms. Data Sources and Searches A research librarian searched multiple electronic databases, including Ovid MEDLINE (January 1990 through June 2015), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (through June 2015). We also reviewed reference lists and searched ClinicalTrials.gov. Study Selection Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria. We included cross-sectional and cohort studies on the diagnostic accuracy of urinary biomarkers in adults who had signs or symptoms of bladder cancer or were undergoing surveillance for recurrent disease after treatment. We focused on urinary biomarkers approved by the FDA for the diagnosis of bladder cancer (quantitative or qualitative NMP22, qualitative or quantitative BTA, FISH, and ImmunoCyt) or classified by the FDA as a laboratory-developed test (Cxbladder). We excluded studies that used a casecontrol design; studies that did not evaluate the diagnostic accuracy of biomarkers against standard diagnostic methods (cystoscopy and histopathology); and studies on the accuracy of biomarkers for screening in assessing prognosis, guiding therapy, or monitoring response to treatment. Data Extraction and Quality Assessment One investigator extracted details about the setting, tests evaluated, definition of a positive test result, study design, reference standard, inclusion criteria, population characteristics, proportion found to have bladder cancer, bladder cancer stage and grade, results, and funding sources. We constructed 22 tables with the number of true-positive, false-positive, true-negative, and false-negative results from published sample sizes, prevalence, sensitivity, and specificity. A second investigator verified extractions for accuracy. Two investigators independently assessed the risk of bias for each study as low, moderate, or high using criteria adapted from QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) (8). Discrepancies were resolved through discussion and consensus. Data Synthesis and Analysis We performed meta-analyses for sensitivity and specificity using a bivariate logistic mixed-effects model (9) with SAS, version 10.0 (SAS Institute) (10). We assumed random effects with a bivariate normal distribution and measured statistical heterogeneity with the random-effects variance (2). When few studies were available for an analysis, we used the moment estimates of correlation between sensitivity and specificity in the bivariate model. We calculated positive and negative likelihood ratios (LRs) using the summarized sensitivity and specificity (11, 12). Because studies of a particular biomarker generally used the same definition for a positive test result, we did not plot summary receiver-operating characteristic curves (13). For head-to-head comparisons, we used the same bivariate logistic mixed-effects model, with an added indicator variable for the tests. We conducted analyses for each biomarker by using data from all patients and data stratified according to whether testing was performed for initial diagnosis (evaluation of symptoms) or diagnosis of recurrence (surveillance). We also performed analyses stratified by study design features (such as retrospective or prospective or use of a prespecified threshold to define a positive test result), risk of bias (overall and whether the study performed blinding to the results of the index test), the country in which the study was conducted, and tumor grade and stage (14). We assessed the strength of evidence (SOE) for each body of evidence as high, moderate, low, or insufficient based on aggregate study quality, precision, consistency, and directness. Role of the Funding Source This project was funded under contract HHSA290201200014I from the AHRQ, U.S. Department of Health and Human Services. AHRQ staff assisted in developing the scope and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis. Results The literature flow diagram (Figure 1) summarizes the search and selection of articles. Database searches resulted in 4358 potentially relevant articles. After dual review of abstracts and titles, we selected 262 articles for full-text dual review and determined that 57 studies (in 60 publications) met our inclusion criteria (Appendix Table 1) (15-74). Nineteen studies evaluated quantitative NMP22, 4 evaluated qualitative NMP22, 23 evaluated qualitative BTA, 4 evaluated quantitative BTA, 10 evaluated FISH, 13 evaluated ImmunoCyt, and 1 evaluated Cxbladder. Sample sizes ranged from 26 to 3916, mean age ranged from 54 to 77 years, the proportion of male patients ranged from 57% to 88%, and the proportion diagnosed with bladder cancer ranged from 3% to 81%. Eight studies focused on diagnostic testing for signs and symptoms suggestive of bladder cancer, 16 focused on surveillance of previously treated bladder cancer, and 19 evaluated mixed populations. Forty-three studies were conducted in the United States or Europe. We rated 2 studies as having low risk of bias (20, 21), 3 as having high risk of bias (25, 62, 68), and the remainder as having medium risk of bias. Frequent methodological shortcomings were failure to report blinded interpretation of the reference standard, failure to report enrollment of a random or consecutive sample of patients, or failure to report predefined criteria for a positive test result. Figure 1. Summary of evidence search and selection. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. Includes prior reports, reference lists of relevant articles, and systematic reviews. Appendix Table 1. Biomarker Study Characteristics Appendix Table 1 Continued Appendix Table 1 Continued Appendix Table 1 Continued Quantitative NMP22 Sensitivity of quantitative NMP22 was 0.69 (95% CI, 0.62 to 0.75), and specificity was 0.77 (CI, 0.70 to 0.83) (19 studies), for a positive LR of 3.05 (CI, 2.28 to 4.10) and a negative LR of 0.40 (CI, 0.32 to 0.50) (Appendix Figure 1). Exclusion of 2 studies that used a cutoff other than >10 U/mL for a positive test result (18, 37) resulted in similar sensitivity and specificity. Diagnostic accuracy was similar for evaluation of symptoms and for surveillance. Excluding 1 study with high risk of bias (68) and restricting the analysis to prospective studies, those conducted in the United States or Europe, or those that used a prespecified threshold for a positive test result had little effect on pooled estimates. Restricting the analysis to 3 studies with blinded reference standard interpretation resulted in higher specificity (0.89 [CI, 0.78 to 0.95]) (15, 42, 58). Appendix Figure 1. Sensitivity and specificity of quantitative NMP22. NMP22 = nuclear matrix protein 22; TN = true-negative; TP = true-positive. Qualitative NMP22 Sensitivity of qualitative NMP22 was 0.58 (CI, 0.39 to 0.75), and specificity was 0.88 (CI, 0.78 to 0.94) (4 studies), for a positive LR of 4.89 (CI, 3.23 to 7.40) and a negative LR of 0.48 (CI, 0.33 to 0.71) (Appendix Figure 2) (20, 21, 23, 37). Restricting the analysis to 2 studies with low risk of bias resulted in similar estimates (sensitivity, 0.53 [CI, 0.29 to 0.75]; specificity, 0.87 [CI, 0.74 to 0.94]) (20, 21). Subgroup and sensitivity analyses were limited by small numbers of studies. Appendix Figure 2. Sensitivity and specificity of qualitative NMP22. NMP22 = nuclear matrix protein 22; TN = true-negative; TP = true-positive. Qualitative BTA Sensitivity of qualit

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.

Intravesical Therapy for the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis

Purpose: We systematically review the benefits and harms of intravesical therapies for nonmuscle invasive bladder cancer. Materials and Methods: Systematic literature searches were performed of Ovid MEDLINE (January 1990 through February 2016), the Cochrane databases and reference lists. Randomized and quasi‐randomized trials of intravesical bacillus Calmette‐Guérin, mitomycin C, gemcitabine, thiotepa, valrubicin, doxorubicin, epirubicin and interferon vs transurethral bladder tumor resection alone, and head‐to‐head trials of intravesical therapies were selected. Data were pooled using a random effects model. Results: Overall 39 trials evaluated adjuvant intravesical therapy vs transurethral bladder tumor resection alone. Bacillus Calmette‐Guérin was associated with a decreased risk of bladder cancer recurrence (3 trials, RR 0.56, 95% CI 0.43–0.71) and progression (4 trials, RR 0.39, 95% CI 0.24–0.64) (strength of evidence low). Mitomycin C, doxorubicin, epirubicin and thiotepa were also associated with a decreased risk of recurrence, with no difference in risk of progression (strength of evidence low). There were 55 trials that compared one intravesical therapy agent against another. There were no differences between bacillus Calmette‐Guérin vs mitomycin C in recurrence risk (RR 0.95, 95% CI 0.81–1.11), but bacillus Calmette‐Guérin was associated with a decreased risk of recurrence in the subgroup of trials of maintenance regimens (RR 0.79, 95% CI 0.71–0.87, strength of evidence low). Bacillus Calmette‐Guérin was associated with a lower recurrence risk vs doxorubicin, epirubicin, interferon alpha‐2a, bacillus Calmette‐Guérin plus interferon alpha‐2b, and thiotepa (strength of evidence low to moderate). Bacillus Calmette‐Guérin was associated with higher rates of local and systemic adverse events than other intravesical agents (strength of evidence low). Head‐to‐head trials showed no clear differences between standard and lower doses of bacillus Calmette‐Guérin in recurrence, progression or mortality risk (strength of evidence low). Limited evidence suggested that bacillus Calmette‐Guérin maintenance regimens are associated with reduced recurrence risk vs no further intravesical therapy in responders to induction therapy (strength of evidence low). Conclusions: For nonmuscle invasive bladder cancer several intravesical therapies are associated with a decreased risk of recurrence vs transurethral bladder tumor resection alone. Bacillus Calmette‐Guérin is the only agent associated with a decreased progression risk vs transurethral bladder tumor resection alone, but may be associated with a higher risk of adverse events than other intravesical therapies, indicating trade‐offs between potential benefits and harms.

Impact of contacting study authors to obtain additional data for systematic reviews: diagnostic accuracy studies for hepatic fibrosis

BackgroundSeventeen of 172 included studies in a recent systematic review of blood tests for hepatic fibrosis or cirrhosis reported diagnostic accuracy results discordant from 2 × 2 tables, and 60 studies reported inadequate data to construct 2 × 2 tables. This study explores the yield of contacting authors of diagnostic accuracy studies and impact on the systematic review findings.MethodsSixty-six corresponding authors were sent letters requesting additional information or clarification of data from 77 studies. Data received from the authors were synthesized with data included in the previous review, and diagnostic accuracy sensitivities, specificities, and positive and likelihood ratios were recalculated.ResultsOf the 66 authors, 68% were successfully contacted and 42% provided additional data for 29 out of 77 studies (38%). All authors who provided data at all did so by the third emailed request (ten authors provided data after one request). Authors of more recent studies were more likely to be located and provide data compared to authors of older studies. The effects of requests for additional data on the conclusions regarding the utility of blood tests to identify patients with clinically significant fibrosis or cirrhosis were generally small for ten out of 12 tests. Additional data resulted in reclassification (using median likelihood ratio estimates) from less useful to moderately useful or vice versa for the remaining two blood tests and enabled the calculation of an estimate for a third blood test for which previously the data had been insufficient to do so. We did not identify a clear pattern for the directional impact of additional data on estimates of diagnostic accuracy.ConclusionsWe successfully contacted and received results from 42% of authors who provided data for 38% of included studies. Contacting authors of studies evaluating the diagnostic accuracy of serum biomarkers for hepatic fibrosis and cirrhosis in hepatitis C patients impacted conclusions regarding diagnostic utility for two blood tests and enabled the calculation of an estimate for a third blood test. Despite relatively extensive efforts, we were unable to obtain data to resolve discrepancies or complete 2 × 2 tables for 62% of studies.

Treatment of muscle‐invasive bladder cancer: A systematic review

There is uncertainty regarding the use of bladder‐sparing alternatives to standard radical cystectomy, optimal lymph node dissection techniques, and optimal chemotherapeutic regimens. This study was conducted to systematically review the benefits and harms of bladder‐sparing therapies, lymph node dissection, and systemic chemotherapy for patients with clinically localized muscle‐invasive bladder cancer. Systematic literature searches of MEDLINE (from 1990 through October 2014), the Cochrane databases, reference lists, and the ClinicalTrials.gov Web site were performed. A total of 41 articles were selected for review. Bladder‐sparing therapies were found to be associated with worse survival compared with radical cystectomy, although the studies had serious methodological shortcomings, findings were inconsistent, and only a few studies evaluated currently recommended techniques. More extensive lymph node dissection might be more effective than less extensive dissection at improving survival and decreasing local disease recurrence, but there were methodological shortcomings and some inconsistency. Six randomized trials found cisplatin‐based combination neoadjuvant chemotherapy to be associated with a decreased mortality risk versus cystectomy alone. Four randomized trials found adjuvant chemotherapy to be associated with decreased mortality versus cystectomy alone, but none of these trials reported a statistically significant effect. There was insufficient evidence to determine optimal chemotherapeutic regimens. Cancer 2016;122:842–51.

Screening for Celiac Disease: Evidence Report and Systematic Review for the US Preventive Services Task Force

Importance Silent or subclinical celiac disease may result in potentially avoidable adverse health consequences. Objective To review the evidence on benefits and harms of screening for celiac disease in asymptomatic adults, adolescents, and children 3 years and older for the US Preventive Services Task Force. Data Sources Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews, searched to June 14, 2016. Study Selection Randomized clinical trials and cohort or case-control studies on clinical benefits and harms of screening vs no screening for celiac disease or treatment vs no treatment for screen-detected celiac disease; studies on diagnostic accuracy of serologic tests for celiac disease. Data Extraction and Synthesis One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. Main Outcomes and Measures Cancer incidence, gastrointestinal outcomes, psychological outcomes, child growth outcomes, health outcomes resulting from nutritional deficiencies, quality of life, mortality, and harms of screening. No meta-analytic pooling was done. Results One systematic review and 3 primary studies met inclusion criteria. No trials of screening for celiac disease were identified. One recent, good-quality systematic review of 56 original studies and 12 previous systematic reviews (sample sizes of primary studies ranging from 62 to more than 12 000 participants) found IgA tissue transglutaminase was associated with high accuracy (sensitivity and specificity both >90%) for diagnosing celiac disease. IgA endomysial antibodies tests were associated with high specificity. Only 2 studies of serologic tests for celiac disease involving 62 and 158 patients were conducted in asymptomatic populations and reported lower sensitivity (57% and 71%). One fair-quality, small (n = 40) Finnish treatment trial of asymptomatic adults with screen-detected celiac disease based on positive serologic findings found initiation of a gluten-free diet associated with small improvement in gastrointestinal symptoms compared with no gluten-free diet (difference less than 1 point on a scale of 1 to 7) at 1 year, with no differences on most measures of quality of life. No withdrawals due to adverse events occurred during the trial; no other harms were reported. No studies were identified that addressed the other outcomes. Conclusions and Relevance Although some evidence was found regarding diagnostic accuracy of tests for celiac disease, little or no evidence was identified to inform most of the key questions related to benefits and harms of screening for celiac disease in asymptomatic individuals. More research is needed to understand the effectiveness of screening and treatment for celiac disease, accuracy of screening tests in asymptomatic persons, and optimal screening strategies.