Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a debilitating multisystem condition characterized by chronic and disabling fatigue and several other symptoms, including pain, sleep disturbance, neurologic and cognitive changes, motor impairment, and altered immune and autonomic responses (13). Experts consider postexertional malaise and memory or concentration problems to be critical components (46), and several diagnostic criteria, including those released by the Institute of Medicine in 2015, require the presence of postexertional malaise (1, 2, 79). There is uncertainty regarding the cause of ME/CFS, whether it is a pathologically discrete syndrome (2, 4), whether ME should be considered a subset of CFS or its own distinct disease (6), and whether symptoms are nonspecific and shared by other disease entities. Some propose that an inciting event initiates an immune response that leads to immune and neuroendocrine dysregulation (10, 11). Viral causes have been studied on the basis of the observation that most patients report a sudden onset of symptoms that were preceded by a febrile illness with enlarged lymph nodes. However, no specific virus or other infectious agent has been identified, and not all patients experience a preceding febrile illness (10). The Centers for Disease Control and Prevention (CDC) reported a 0.3% prevalence of ME/CFS in the United States in 1997, corresponding to more than 1 million adults (12). Through use of different case definitions or different diagnostic methods, the rate may be as high as 3.3% (13, 14). Given the multitude of symptoms that patients with ME/CFS experience, treatment approaches have been broad, including immunologic, pharmacologic, and behavioral treatments and complementary and alternative medicine. No medications for the treatment of ME/CFS have been approved by the U.S Food and Drug Administration (FDA); however, many have been used without review and approval (off-label), and some are not approved for any indication in the United States (for example, isoprinosine and rintatolimod). In an FDA survey, patients with ME/CFS identified treatments that fell into 2 broad categories: those intended to treat the cause of the disease and those targeting specific symptoms or perpetuating factors (15). Medications to treat causes include immune modulators, antivirals, and antibiotics. Interventions targeting symptoms include medications to treat specific symptoms, such as pain, fatigue, autonomic dysfunction, and sleep dysfunction, and nondrug therapies, such as yoga, exercise techniques, counseling, pacing strategies, and mental exercises (15). In practice, the clinical management of patients varies widely, and many patients receive a multifaceted approach to treatment. This systematic review is part of a larger report to inform a research agenda for the National Institutes of Health (NIH) 2014 Pathways to Prevention Workshop, an evidence-based methodology workshop (16). This review evaluates and summarizes research on the benefits and harms of medical and nonmedical treatments for ME/CFS based on trials enrolling patients meeting criteria for ME, CFS, or both and identifies limitations of current studies and needs for future research in this area. Methods Key questions guiding this review were developed in collaboration with the NIH ME/CFS Working Group following a standard protocol, including input from key informants and a technical expert panel, registration in the PROSPERO database for systematic reviews (17), and posting on an Agency for Healthcare Research and Quality (AHRQ) public Web site. Key questions concern the benefits and harms of therapeutic interventions for adults with ME/CFS, how interventions vary by patient subgroups, and characteristics of patients who respond and do not respond to interventions. A technical report details the methods and includes the analytic framework, search strategies, and additional evidence tables (16). Data Sources and Searches A research librarian searched the following electronic databases to identify relevant articles published between January 1988 (year of first case definition) and September 2014: MEDLINE (Ovid), PsycINFO, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and National Health Sciences Economic Evaluation Database. Searches were supplemented by references identified from additional sources, including trial registries, scientific information packets from manufacturers, reference lists, and experts. Study Selection We included English-language trials that enrolled patients aged 18 years or older who met the criteria for ME, CFS, or both according to at least 1 established case definition. Included were randomized, controlled trials of at least 12 weeks' duration that compared medications, complementary and alternative medicine approaches, counseling and behavior therapies, and exercise therapies with no treatment or other types of treatment. For completeness, we separately summarized additional trials of medications that were designed for shorter durations of treatment. Treatment outcomes were patient centered and included function, fatigue, quality of life, involvement in daily activities, and harms. We did not include studies of the results of laboratory tests or studies focusing on individual symptoms, such as pain. Two investigators independently evaluated each study to determine inclusion eligibility. Disagreement was resolved by consensus, with a third investigator making the final decision as needed. Data Extraction and Quality Assessment From the included studies, one investigator extracted study details and a second investigator reviewed them for accuracy and completeness. Investigators rated the quality (risk of bias) of the individual studies and strength of the body of evidence on the basis of established criteria (18). The strength of evidence consisted of 4 major categorieshigh, moderate, low, or insufficientaccording to the design, quantity, size, and quality of studies; consistency across studies; precision of estimates; and directness of effect. A second investigator reviewed ratings, and disagreements were resolved by consensus, with a third investigator making the final decision as needed. Data Synthesis For most treatments, only single trials were available; data were synthesized qualitatively with attention to such factors as patient characteristics and risk of bias. For treatments with more than 2 trials, the appropriateness of statistical meta-analysis was determined by considering internal validity of the studies and the heterogeneity among studies in design, patient population, interventions, and outcomes. The combined effects were estimated by using a random-effects model based on the profile likelihood method (19). Combined relative risks were calculated for binary outcomes. For continuous outcomes, the combined weighted mean differences were calculated by using the means and SDs at follow-up from each intervention group. The chi-square test based on the Q statistic and the I 2 statistic (the proportion of variation in study estimates due to heterogeneity) were used to assess heterogeneity in effects between studies, and sensitivity analyses explored statistical heterogeneity when present. All quantitative analyses were performed by using Stata/IC software, version 13.0 (Stata Corp.). Role of the Funding Source The AHRQ funded the review, and a working group convened by the NIH helped develop the review's scope and key questions. Neither had a role in study selection, quality assessment, or synthesis. The investigators are solely responsible for the content. Results Among the 6175 abstracts identified by searches, 35 treatment trials in 45 publications met inclusion criteria (Appendix Figure). These included 9 trials of medications (2028), 7 of complementary and alternative medicine (2935), 14 of counseling or behavioral therapies (8, 3648), 7 of exercise (23, 4854), and 4 comparing or combining different therapies (23, 40, 48, 53) (Appendix Table 1). Most trials met criteria for fair quality (24 trials) or poor quality (5 trials). Trials enrolled predominantly middle-aged women from ME/CFS specialty clinics; used CFS case definitions, primarily the 1994 CDC (3) or Oxford criteria (56), to determine participant eligibility; had small sample sizes (27 trials had <100 participants); and were conducted in the United States and Western Europe (16). Outcomes varied across trials and included 20 unique measures as well as various Likert scales developed for individual studies. Even when trials used the same outcome, measures and thresholds were often defined differently, thereby limiting comparisons and statistical meta-analysis. In general, harms were rarely reported. Appendix Figure. Summary of evidence search and selection. CAM = complementary and alternative medicine; CBT = cognitive behavioral therapy. * Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment, National Health Sciences Economic Evaluation Database, and the Cochrane Database of Systematic Reviews. Identified from such sources as reference lists, hand searches, and suggestions by experts. Studies that provided data and contributed to the body of evidence were considered "included." Studies may be included in more than 1 published article, and this number indicates the number of unique studies included, representing a total of 45 publications. Studies may have provided data for more than 1 type of treatment. Studies included for the diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome are reported in the companion article in this issue (71). Appendix Table 1. Summary of Trials of Therapies Major limitations of trials included enrollment of fewer than 20 participants in a study group (8, 20, 25, 2830), dissimilar groups at baseline (31, 43, 5

IN RESPONSE: We thank the authors for their comments and Dr. Speedy for sharing his personal experience. Regarding Dr. White and colleagues' statements about the harms of exercise, we acknowledge that exercise testing differs from graded exercise programs. However, patients may consider both forms of exercise harmful. To clarify the results of Moss-Morris and associates' trial, whereas 44% of participants in the intervention group declined repeated exercise testing, 20% did so because of their perception of harm (1). Also, although the Cochrane review did not identify harms of exercise, the authors drew similar conclusions to ours, stating that, limited information makes it difficult to draw firm conclusions about the safety of exercise therapy (2). To address Dr. Chu and coworkers' comment about safety data in Nez and colleagues' trial, we agree that the intervention group reported a decline in physical function and increase in pain. However, the trial reported within-group differences and not between-group differences (3), which are necessary to support results of comparisons of interventions in the trial. Their statement about the importance of analyzing data on the basis of case definitions used for inclusion in trials is consistent with our approach. For example, in the CBT trials using the physical function item of the 36-item Short-Form Survey as an outcome measure, the 2 studies using the Oxford criteria indicated improvement, whereas the 2 using the CDC criteria reported no improvement. We also agree with Dr. White and colleagues that combining counseling and CBT trials in a meta-analysis may dilute the individual effectiveness of each intervention, which is why our meta-analysis included only trials of CBT. We excluded from our analysis the studies referenced by Dr. Chu and coworkers and Mr. Kirby about the comparative effectiveness of CBT and GET and predictors of outcomes because they included participants with chronic fatigue rather than ME/CFS (4, 5). One of the studies found that 31% of their fatigued participants met criteria for CFS (according to the CDC Fukuda criteria [ 5]). Although those with CFS had more fatigue and functional impairment than other participants, the authors did not compare case definitions or evaluate outcomes for those with CFS on the basis of intervention.

BACKGROUND:Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a debilitating multisystem condition affecting more than 1 million adults in the United States.PURPOSE:To determine benefits and harms of treatments for adults with ME/CFS and identify future research needs.DATA SOURCES:MEDLINE, PsycINFO, and Cochrane databases (January 1988 to September 2014); clinical trial registries; reference lists; and manufacturer information.STUDY SELECTION:English-language randomized trials of the effectiveness and adverse effects of ME/CFS treatments.DATA EXTRACTION:Data on participants, study design, analysis, follow-up, and results were extracted and confirmed. Study quality was dual-rated by using prespecified criteria; discrepancies were resolved through consensus.DATA SYNTHESIS:Among 35 treatment trials enrolling participants primarily meeting the 1994 Centers for Disease Control and Prevention and Oxford case definitions of CFS, the immune modulator rintatolimod improved some measures of exercise performance compared with placebo in 2 trials (low strength of evidence). Trials of galantamine, hydrocortisone, IgG, valganciclovir, isoprinosine, fluoxetine, and various complementary medicines were inconclusive (insufficient evidence). Counseling therapies and graded exercise therapy compared with no treatment, relaxation, or support improved fatigue, function, global improvement, and work impairment in some trials; counseling therapies also improved quality of life (low to moderate strength of evidence). Harms were rarely reported across studies (insufficient evidence).LIMITATION:Trials were heterogeneous and were limited by size, number, duration, applicability, and methodological quality.CONCLUSION:Trials of rintatolimod, counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for other treatments and harms is insufficient. More definitive studies comparing participants meeting different case definitions, including ME, and providing subgroup analysis are needed to fill research gaps.

s of potentially relevant articles identified through MEDLINE, PsycINFO, Cochrane*, and other sources† (n = 6175) Medication: 9 Exercise: 7 Combination: 4 Articles excluded (n = 988) Study does not address a key question or meet inclusion criteria, but full text pulled to provide background information: 391 Wrong population: 81 Wrong intervention: 15 Wrong outcomes: 99 Wrong study design: 142 Wrong publication type: 171 Foreign language: 1 Inadequate duration: 59 Study published before 1988: 1 Systematic review not meeting requirements: 28 Final included studies (n = 71)‡ (81 publications) Full-text articles reviewed for relevance to key questions (n = 1069) Excluded abstracts and background articles (n = 5106) Diagnosis (n = 36)|| Treatment (n = 35)§ CAM: 7 CBT: 14 CAM = complementary and alternative medicine; CBT = cognitive behavioral therapy. * Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment, National Health Sciences Economic Evaluation Database, and the Cochrane Database of Systematic Reviews. † Identified from such sources as reference lists, hand searches, and suggestions by experts. ‡ Studies that provided data and contributed to the body of evidence were considered “included.” § Studies may be included in more than 1 published article, and this number indicates the number of unique studies included, representing a total of 45 publications. Studies may have provided data for more than 1 type of treatment. || Studies included for the diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome are reported in the companion article in this issue (71). Annals of Internal Medicine www.annals.org Annals of Internal Medicine • Vol. 162 No. 12 • 16 June 2015 Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/934140/ on 04/28/2017 A p p en di x Ta bl e 1. Su m m ar y o fT ri al s o fT he ra p ie s

None of the current diagnostic methods have been adequately tested to identify patients with ME/CFS when diagnostic uncertainty exists. Rintatolimod improves exercise performance in some patients (low strength of evidence), while counseling therapies and GET have broader benefit but have not been adequately tested in more disabled populations (low to moderate strength of evidence). Other treatments and harms have been inadequately studied (insufficient evidence). More definitive studies are needed to fill the many research gaps in diagnosing and treating ME/CFS.

RATIONALEEarly warning system (EWS) scores are used by hospital care teams to recognize early signs of clinical deterioration and trigger more intensive care.OBJECTIVETo systematically review the evidence on the ability of early warning system scores to predict a patient's risk of clinical deterioration and the impact of early warning system implementation on health outcomes and resource utilization.METHODSWe searched the MEDLINE, CINAHL, and Cochrane Central Register of Controlled Trials databases through May 2014. We included English-language studies of early warning system scores used with adults admitted to medical or surgical wards. We abstracted study characteristics, including population, setting, sample size, duration, and criteria used for early warning system scoring. For predictive ability, the primary outcomes were modeled for discrimination on 48-hour mortality, cardiac arrest, or pulmonary arrest. Outcomes for the impact of early warning system implementation included 30-day mortality, cardiovascular events, use of vasopressors, respiratory failure, days on ventilator, and resource utilization. We assessed study quality using a modified Quality in Prognosis Studies assessment tool where applicable.MEASUREMENTS AND MAIN RESULTSOf 11,183 citations studies reviewed, one controlled trial and 20 observational studies of 13 unique models met our inclusion criteria. In eight studies, researchers addressed the predictive ability of early warning system tools and found a strong predictive value for death (area under the receiver operating characteristic curve [AUROC], 0.88-0.93) and cardiac arrest (AUROC, 0.74-0.86) within 48 hours. In 13 studies (one controlled trial and 12 pre-post observational studies), researchers addressed the impact on health outcomes and resource utilization and had mixed results. The one controlled trial was of good quality, and the researchers found no difference in mortality, transfers to the ICU, or length of hospital stay. The pre-post designs of the remaining studies have significant methodological limitations, resulting in insufficient evidence to draw conclusions.CONCLUSIONSEarly warning system scores perform well for prediction of cardiac arrest and death within 48 hours, although the impact on health outcomes and resource utilization remains uncertain, owing to methodological limitations. Efforts to assess performance and effectiveness more rigorously will be needed as early warning system use becomes more widespread.

BACKGROUND:Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low. PURPOSE:To update evidence about the effectiveness and adverse effects of medications to reduce breast cancer risk, patient use of such medications, and methods for identifying women at increased risk for breast cancer. DATA SOURCES:MEDLINE and Cochrane databases (through 5 December 2012), Scopus, Web of Science, clinical trial registries, and reference lists. STUDY SELECTION:English-language randomized trials of medication effectiveness and adverse effects, observational studies of adverse effects and patient use, and diagnostic accuracy studies of risk assessment. DATA EXTRACTION:Investigators independently extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability using established criteria. DATA SYNTHESIS:Seven good- and fair-quality trials indicated that tamoxifen and raloxifene reduced incidence of invasive breast cancer by 7 to 9 cases in 1000 women over 5 years compared with placebo. New results from STAR (Study of Tamoxifen and Raloxifene) showed that tamoxifen reduced breast cancer incidence more than raloxifene by 5 cases in 1000 women. Neither reduced breast cancer-specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms. Thirteen risk-stratification models were modest predictors of breast cancer. LIMITATION:Data on mortality and adherence measures and for women who are nonwhite, are premenopausal, or have comorbid conditions were lacking. CONCLUSION:Medications reduced the incidence of invasive breast cancer and fractures and increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene but also increased the incidence of endometrial cancer and cataracts. Use is limited by adverse effects and inaccurate methods to identify candidates. PRIMARY FUNDING SOURCE:Agency for Healthcare Research and Quality.

Objectives Pressure ulcers affect up to 3 million Americans and are a major source of morbidity, mortality, and health care cost. This review summarizes evidence comparing the effectiveness and safety of pressure ulcer treatment strategies. Data sources Articles published between January 1, 1985, and October 17, 2012, were identified from searches of MEDLINE® (Ovid), Embase (Elsevier), CINAHL (EBSCOhost), EBM Reviews (Ovid), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and Health Technology Assessment. Additional studies were identified by searching reference lists from included studies and systematic reviews of pressure ulcer treatments. Gray literature, including unpublished data, abstracts, dissertations, and individual product packets from manufacturers, was also reviewed. Review methods The literature, quality of included studies, and extracted data were dual-reviewed using predefined criteria. Results were summarized in evidence tables. Summary results were derived primarily from qualitative analysis and synthesis. Results We reviewed 7,274 titles and abstracts and 1,836 full-length articles. We included 174 studies (trials and observational studies) addressing the effectiveness and/or harms of different treatments for pressure ulcers. These studies examined a wide range of interventions, but sample sizes often were small. We found moderate-strength evidence that some interventions were associated with wound improvement, including the use of air-fluidized beds (compared with other support surfaces), protein-containing nutritional supplements (compared with placebos or other routine measures of nutritional support), radiant heat dressings (compared with other dressings), and electrical stimulation (compared with a sham treatment). Several other interventions had limited evidence of effectiveness (strength of evidence rated as low). Only a minority of studies examined complete wound healing as an outcome. In general, the evidence about the harms of any of these treatments was limited. Limitations Most studies were of poor quality and had followup periods inadequate to assess complete wound healing. Studies often measured healing outcomes using heterogeneous methods, making it difficult to compare results across studies. Conclusions There was limited evidence to draw firm conclusions about the best approaches for treating pressure ulcers, a finding consistent with other recent reviews on this topic. Future research with larger sample sizes, more rigorous adherence to methodological standards for clinical trials, longer followup periods, and more standardized and clinically meaningful outcome measures is needed to inform clinical practice and policy.