Hau Liu

Are Organic Foods Safer or Healthier Than Conventional Alternatives?: A Systematic Review

BACKGROUND The health benefits of organic foods are unclear. PURPOSE To review evidence comparing the health effects of organic and conventional foods. DATA SOURCES MEDLINE (January 1966 to May 2011), EMBASE, CAB Direct, Agricola, TOXNET, Cochrane Library (January 1966 to May 2009), and bibliographies of retrieved articles. STUDY SELECTION English-language reports of comparisons of organically and conventionally grown food or of populations consuming these foods. DATA EXTRACTION 2 independent investigators extracted data on methods, health outcomes, and nutrient and contaminant levels. DATA SYNTHESIS 17 studies in humans and 223 studies of nutrient and contaminant levels in foods met inclusion criteria. Only 3 of the human studies examined clinical outcomes, finding no significant differences between populations by food type for allergic outcomes (eczema, wheeze, atopic sensitization) or symptomatic Campylobacter infection. Two studies reported significantly lower urinary pesticide levels among children consuming organic versus conventional diets, but studies of biomarker and nutrient levels in serum, urine, breast milk, and semen in adults did not identify clinically meaningful differences. All estimates of differences in nutrient and contaminant levels in foods were highly heterogeneous except for the estimate for phosphorus; phosphorus levels were significantly higher than in conventional produce, although this difference is not clinically significant. The risk for contamination with detectable pesticide residues was lower among organic than conventional produce (risk difference, 30% [CI, -37% to -23%]), but differences in risk for exceeding maximum allowed limits were small. Escherichia coli contamination risk did not differ between organic and conventional produce. Bacterial contamination of retail chicken and pork was common but unrelated to farming method. However, the risk for isolating bacteria resistant to 3 or more antibiotics was higher in conventional than in organic chicken and pork (risk difference, 33% [CI, 21% to 45%]). LIMITATION Studies were heterogeneous and limited in number, and publication bias may be present. CONCLUSION The published literature lacks strong evidence that organic foods are significantly more nutritious than conventional foods. Consumption of organic foods may reduce exposure to pesticide residues and antibiotic-resistant bacteria. PRIMARY FUNDING SOURCE None.

Systematic Review: A Century of Inhalational Anthrax Cases from 1900 to 2005

Key Summary Points Initiation of antibiotic or anthrax antiserum therapy during the prodromal phase of inhalational anthrax is associated with an improved short-term survival. Multidrug antibiotic regimens are associated with decreased mortality, especially when they are administered during the prodromal phase. Most surviving patients will probably require drainage of reaccumulating pleural effusions. Despite modern intensive care, fulminant-phase anthrax is rarely survivable. The 2001 anthrax attack demonstrated the vulnerability of the United States to anthrax bioterrorism. The mortality rate observed during the 2001 U.S. attack (45%) was considerably lower than that historically reported for inhalational anthrax (89% to 96%) (1, 2). This reduction generally is attributed to the rapid provision of antibiotics and supportive care in modern intensive care units (3). However, no comprehensive reviews of reports of inhalational anthrax cases (including those from 2001) that evaluate how patient factors and therapeutic interventions affect disease progression and mortality have been published. Before the introduction of antibiotics, anthrax infection was primarily treated with antiserum (4). Anthrax antiserum reportedly decreased mortality by 75% compared with no treatment (5-8), and its efficacy is supported by recent animal data (9). Later, effective antibiotics, such as penicillin and chloramphenicol, were added to anthrax treatment strategies (10, 11). Currently, combination antibiotic therapy with ciprofloxacin (or doxycycline), rifampin, and clindamycin is recommended on the basis of anecdotal evidence from the U.S. 2001 experience (1, 12, 13). Historically, the clinical course of untreated inhalational anthrax has been described as biphasic, with an initial benign prodromal latent phase, characterized by a nonspecific flu-like syndrome, followed by a severe fulminant acute phase, characterized by respiratory distress and shock that usually culminates in death (2, 14). The duration of the prodromal phase has been reported to range from 1 to 6 days (14, 15), whereas that of the fulminant phase has been described as less than 24 hours (14, 16). A 1957 study confirmed these estimates of disease progression but was based on only 6 patients (17). Because a report synthesizing the data from all reported cases of inhalational anthrax (including those from 2001) has not been published, we do not have accurate estimates of the time course associated with disease progression or a clear understanding of the extent to which patient characteristics and treatment factors affect disease progression and mortality. This information is important for developing appropriate treatment and prophylaxis protocols and for accurately simulating anthrax-related illness to inform planning efforts for bioterrorism preparedness. We systematically reviewed published cases of inhalational anthrax between 1900 and 2005 to evaluate the effects of patient factors (for example, age and sex) and therapeutic factors (for example, time to onset of treatment) on disease progression and mortality. Methods Literature Sources and Search Terms We searched MEDLINE to identify case reports of inhalational anthrax (January 1966 to June 2005) by using the Medical Subject Heading (MeSH) terms anthrax and case reports. Because many reports were published before 1966 (the earliest publication date referenced in MEDLINE), we performed additional comprehensive searches of retrieved bibliographies and the indexes of 14 selected journals from 1900 to 1966 (for example, New England Journal of Medicine, The Lancet, La Presse Mdicale, Deutsche Medizinische Wochenschrift, and La Semana Mdica) to obtain additional citations. We considered all case reports of inhalational anthrax to be potentially eligible for inclusion, regardless of language. Study Selection We considered a case report to be eligible for inclusion if its authors established a definitive diagnosis of inhalational anthrax. Appendix Table 1 presents the details of our inclusion criteria. We excluded articles that described cases presenting before 1900 because Bacillus anthracis was not identified as the causative agent of clinical inhalational anthrax until 1877 (18) and because the use of reliable microscopic (19) and culture examination techniques (20) to confirm the diagnosis were not developed until the late 19th century. Appendix Table 1. Inclusion Criteria Data Abstraction One author screened potentially relevant articles to determine whether they met inclusion criteria. Two authors independently abstracted data from each included English-language article and reviewed bibliographies for additional potentially relevant studies. One author abstracted data from nonEnglish-language articles. We resolved abstraction discrepancies by repeated review and discussion. If 2 or more studies presented the same data from 1 patient, we included these data only once in our analyses. We abstracted 4 types of data from each included article: year of disease onset, patient information (that is, age, sex, and nationality), symptom and disease progression information (for example, time of onset of symptoms, fulminant phase, and recovery or death and whether the patient developed meningitis), and treatment information (for example, time and disease stage of the initiation of appropriate treatment and hospitalization). We based our criteria for determining whether a patient had progressed from the prodromal phase to the fulminant phase on distinguishing clinical features of five 2001 (3, 21, 22) and five 1957 (17) cases of fulminant inhalational anthrax. The fulminant phase is described historically as a severe symptomatic disease characterized by abrupt respiratory distress (for example, dyspnea, stridor, and cyanosis) and shock. Meningoencephalitis has been reported to occur in up to 50% of cases of fulminant inhalational anthrax (23). We considered any patient who had marked cyanosis with respiratory failure, who needed mechanical ventilation, who had meningoencephalitis, or who died as having been in the fulminant phase of disease. We used the reported time of an acute change in symptoms or deteriorating clinical picture to estimate when a confirmed fulminant case had progressed from the prodromal phase. We considered therapy for inhalational anthrax to be appropriate if either an antibiotic to which anthrax is susceptible was given (by oral, intramuscular, or intravenous routes) (24-27) or anthrax antiserum therapy was initiated. We classified patients who received antibiotics that are resistant to strains of B. anthracis (<70% susceptibility) as having received no antibiotics. If treatment with antibiotics or antiserum was given, we assumed that the treatment was appropriately dosed and administered. Statistical Analyses We used univariate analyses with SAS software, version 9.1 (SAS Institute Inc., Cary, North Carolina), to summarize the key patient and treatment characteristics. We compared categorical variables with the Fisher exact test and continuous variables with a 2-tailed WilcoxonMannWhitney test. For single comparisons, we considered a P value less than 0.05 to be statistically significant. When comparing U.S. 2001 with pre-2001 cases (or comparing patients who lived with those who died), we applied a Bonferroni correction to account for multiple comparisons (we considered P< 0.025 to be statistically significant: 0.05/2 = 0.025). We computed correlations for pairs of predictors available for each case at the beginning of the course of disease. Adjustments for Censored Data Infectious disease data are subject to incomplete observations of event times (that is, to censoring), particularly in the presence of therapeutic interventions. This can lead to invalid estimation of relevant event time distributions. For example, patients with longer prodromal stage durations are more likely to receive antibiotics than patients with shorter prodromal stage durations, and they may be, therefore, less likely to progress to fulminant stage or death. To account for censoring of our time data, we used maximum likelihood estimates by using both Weibull and log-normal distributions (28). The Appendix provides a detailed description of these analyses. Evaluating Predictors of Disease Progression and Mortality We used a multivariate Cox proportional hazards model to evaluate the prognostic effects of the following features on survival: providing antibiotics or antiserum (a time-dependent covariate in 3 categories: none, single-drug regimen, or multidrug regimen); the stage during which treatment with antibiotics or antiserum was initiated (prodromal stage vs. fulminant stage or no therapy); age (continuous variable); sex; if therapy was given, whether patients received a multidrug regimen (for example, 2 appropriate antibiotics or combination antibioticanthrax antiserum therapy); the use of pleural fluid drainage (a time-dependent covariate); development of anthrax meningoencephalitis (a time-dependent covariate); and whether the case was from the 2001 U.S. attack. We assessed each variable by stepwise backward regression using a P value cutoff of 0.100 or less. We excluded 8 adult patients for whom age was not reported. Although we did not perform extensive goodness-of-fit tests of our models, we did at least fit models in which we entered time not only linearly but also quadratically. Improvement in fit, as judged by conventional Wald and other tests, did not result, nor did including quadratic time variables further explain the data. To estimate mortality as a function of duration from symptom onset to antibiotic initiation, we first calculated a disease progression curve describing the time from symptom onset to fulminant phase among untreated patients by using the Weibull maximum likelihood estimates from the 71 cases for which time estimates were known. We then assigned a mortality rate to patients who had treatmen

Systematic Review: The Effects of Growth Hormone on Athletic Performance

The use of human growth hormone to improve athletic performance has recently received worldwide attention. This practice, often called sports doping, is banned by most professional sports leagues and associations, including the International Olympic Committee, Major League Baseball, and the National Football League (13). However, a wide range of athletes, including those from baseball (46), cycling (7, 8), and track and field (5, 9), have been implicated in or have confessed to illicit growth hormone use. The Mitchell report (10) recently identified 89 Major League Baseball players who allegedly used performance-enhancing drugs, and some of these players have subsequently admitted to using growth hormone (11, 12). Part of the attraction of using growth hormone as a performance enhancer has been that its use is difficult to detect. The World Anti-Doping Agency, whose formation stemmed from the widely publicized doping scandal of the 1998 Tour de France (13), first used a blood test to detect exogenous growth hormone during the 2004 Olympic Games in Athens. However, according to the World Anti-Doping Agency, there have been no test-confirmed positive cases for growth hormone doping in professional or Olympic athletes (14), probably because of the limited availability and implementation of this test. Although growth hormone is reportedly used to enhance athletic performance and has been called the most anabolic substance known (15), its efficacy for this purpose is not well established. Some have suggested that growth hormone is a wonder drug (16) that results in ripped muscle (17) and provides stamina-increasing properties (18). Exogenous growth hormone therapy in growth hormonedeficient adults (that is, those with growth hormone deficiency due to hypothalamic or pituitary defects) results in increased lean mass and decreased fat mass (19), and comparable body composition changes are seen in healthy elderly adults who receive growth hormone (20). Some experts, however, have suggested that the strength-enhancing properties of growth hormone among healthy adults have been exaggerated (15). Serious side effects, including diabetes, hepatitis, and acute renal failure, may occur in athletes using high-dose growth hormone (21). Furthermore, the use of growth hormone for athletic enhancement is not approved by the U.S. Food and Drug Administration, and the distribution of growth hormone for this purpose is illegal in the United States (22). We performed a systematic review of randomized, controlled trials to determine the effects of growth hormone therapy on athletic performance in healthy, physically fit, young adults. Our primary aim was to evaluate the effects of growth hormone on body composition, strength, basal metabolism, and exercise capacity. In addition, we sought to synthesize the evidence on adverse events associated with growth hormone in the healthy young and assess the quality of the published literature. Methods Literature Searches In consultation with 2 research librarians, we developed individual search strategies to identify potentially relevant studies from the MEDLINE, EMBASE, SPORTDiscus, and Cochrane Collaboration databases. We sought English-language reports indexed through 11 October 2007 with keywords including growth hormone and randomized, controlled trial (Appendix Table 1). We searched bibliographies of retrieved articles for additional studies. Appendix Table 1. Search Strategy Study Selection We sought randomized, controlled trials, including crossover trials, that compared growth hormone therapy with no growth hormone therapy. We included studies that 1) evaluated at least 5 participants, 2) enrolled only community-dwelling participants, 3) assessed participants with a mean or median age between 13 and 45 years, and 4) provided data on at least 1 clinical outcome of interest. We excluded studies that 1) focused solely on evaluating growth hormone secretagogues, 2) explicitly included patients with any comorbid medical condition, or 3) evaluated growth hormone as treatment for a specific illness (for example, adult growth hormone deficiency or fibromyalgia). Data Abstraction One author reviewed the titles and abstracts of articles identified through our search and retrieved potentially relevant studies. An endocrinologist and a physician with training in meta-analytic techniques separately reviewed the retrieved studies and abstracted data independently onto pretested abstraction forms. We resolved abstraction differences by repeated review and consensus. If a study did not present data necessary for analysis or mentioned results but did not present data, we requested additional data from study authors. If data were presented graphically, we used the graph-digitizing program DigitizeIt, version 1.5 (Share It, Braunschweig, Germany), to abstract data from the graph (23). If multiple studies presented findings from the same cohort, we used these data only once in our analysis. We abstracted 4 types of data from each study: participant characteristics (for example, age, sex, body mass index, baseline maximum oxygen uptake [VO2max]), study interventions (for example, dose, route, frequency, and duration of growth hormone therapy), study quality (for example, quality of randomization and blinding) (24, 25), and clinical outcomes. We included studies that provided data on at least 1 of the following clinical outcomes: body composition (for example, body weight, lean body mass, fat mass), strength (for example, biceps or quadriceps strength), basal metabolism (for example, resting energy expenditure, basal metabolic rate, heart rate, respiratory exchange ratio, or respiratory quotient), exercise capacity (for example, exercising lactate levels, exercising respiratory exchange ratio or respiratory quotient, maximum inspiratory pressure, bicycling speed, and VO2max), or adverse events. Because the terms lean body mass and fat-free mass are typically used interchangeably in the literature, we report fat-free mass and lean body mass data as a single category of lean body mass. Similarly, we report resting energy expenditure and basal metabolic rate as a single category of basal metabolic rate. Quantitative Data Synthesis To describe key study characteristics, we computed mean values weighted by the number of participants in the trial. To evaluate the effects of growth hormone on body composition and strength, we computed a change score for each clinical outcome for both the treatment and control groups as the value of the outcome at trial end minus the value of the outcome at trial start. We used these change scores to calculate the weighted mean difference and standard mean difference (26) effect sizes. The weighted mean difference is reported in the same units as the clinical outcome of interest, thereby facilitating clinical interpretation. Because our outcomes were similar for both methods, we present only the outcomes from the weighted mean difference method. For studies that did not report the variance of an outcome at trial end minus the value at trial start, we calculated it as the sum of the trial-start and trial-end variances minus twice the covariance (20, 27). Because trial-start data were not available for most of the studies reporting basal metabolic outcomes, we compared trial-end results between treatment and control groups for these outcomes. We combined studies by using random-effects models (2628) because of potential interstudy heterogeneity. The considerable variability in exercise protocols used in the included studies reporting exercise capacity outcomes made pooling these results inappropriate. Instead, we provide a narrative, qualitative assessment of exercise capacity outcomes and report their associated published P values. The variability in reporting adverse events among included studies also made a quantitative meta-analysis of these outcomes inappropriate. Instead, we calculated the proportions of adverse events among participants who received and did not receive growth hormone in studies that reported or evaluated for each adverse event. We performed sensitivity analyses and assessed interstudy heterogeneity to evaluate the robustness of our results. We removed each study individually to evaluate that studys effect on the summary estimates. We assessed publication bias by constructing funnel plots and calculated the number of unpublished studies required to statistically significantly change our results (28). We assessed heterogeneity among study results for each of the summary effects by calculating the Q statistic (and associated P value) and I 2 statistic (26, 2830). We evaluated heterogeneity through predetermined subgroup analysis that stratified studies by duration of treatment. We performed analyses by using Stata software, version 9.1 (Stata, College Station, Texas); SPSS, version 15.0 (SPSS, Chicago); and Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, New Jersey). We considered P values less than 0.05 (2-tailed) to indicate statistically significant differences. Role of the Funding Source The authors were supported in part or fully by the Agency for Healthcare Research and Quality, Santa Clara Valley Medical Center, the U.S. Department of Veteran Affairs, Stanford University Medical Center, Stanford University, Genentech, the National Science Foundation, and the Evidence-Based Medicine Center of Excellence of Pfizer. These funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Results The Figure summarizes the results of our literature searches. We reviewed 7599 titles from the MEDLINE, EMBASE, SPORTDiscus, and the Cochrane Collaboration databases. From our search, we reviewed 252 abstracts in detail and retrieved 56 articles for full-text evaluation.

Elevated late‐night salivary cortisol levels in elderly male type 2 diabetic veterans

Objective  Late‐night salivary cortisol (LNSC) is reportedly highly accurate for the diagnosis of Cushings syndrome (CS). However, diagnostic thresholds for abnormal results are based on healthy, young populations and limited data are available on its use in elderly populations with chronic medical conditions. The purpose of this study was to evaluate LNSC levels in elderly male veterans with and without diabetes.

Meta-analysis: accuracy of quantitative ultrasound for identifying patients with osteoporosis

Context Can calcaneal quantitative ultrasound accurately identify adults with osteoporosis? Contribution This meta-analysis of 25 studies summarizes current knowledge about the accuracy of calcaneal quantitative ultrasound for identifying adults with a dual-energy x-ray absorptiometry (DXA) T-score of 2.5 or less at the hip or spine. The authors found no quantitative ultrasound thresholds at which sensitivity or specificity was sufficiently high to rule out or rule in DXA-determined osteoporosis. Cautions These studies did not evaluate benefits or harms of including quantitative ultrasound in screening programs. Implications Calcaneal quantitative ultrasound results at commonly used thresholds do not definitively exclude or confirm DXA-determined osteoporosis. The Editors Osteoporosis, a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (1), affects approximately 200 million people worldwide (2). In the United States, osteoporosis affects approximately 10 million persons, contributes to 1.5 million fractures annually, and accounted for direct costs of

Successful long-term treatment of Cushing disease with mifepristone (RU486).

18 billion in 2002 (3). Although medical therapies for patients with osteoporosis are available and reduce fracture risk (4-10), most affected individuals are asymptomatic, undiagnosed, and untreated (11). Several organizations, including the U.S. Preventive Services Task Force (12), recommend screening; however, there is no consensus on how to screen patients for osteoporosis. Dual-energy x-ray absorptiometry (DXA) is the most widely used method for diagnosing osteoporosis in most countries (13). This test involves positioning the body site of interest in the path of an x-ray beam and measuring beam attenuation, which is related to bone mineral content. Bone mineral density (BMD) is calculated as the ratio of bone content to the scanned area (14). The World Health Organizations (WHO) operational definition for osteoporosis is a BMD that is 2.5 SDs (T-scores) or more below the mean for young healthy adult women; the WHOs operational definition of osteopenia is a T-score between 1 and 2.5 (15). Numerous DXA devices are currently in use. Correlation between DXA BMD measurements obtained at the same central site (lumbar spine or femoral neck) with different devices has been reported to be 0.92 to 0.99 in several studies (16-19). Recently, there has been increased interest in the use of quantitative ultrasound for osteoporosis screening. Calcaneal quantitative ultrasound for bone assessment typically involves placing ultrasound transducers on either side of the calcaneus; one acts as a wave transmitter, and the other acts as the receiver (20). These devices assess 3 main types of parameters: broadband ultrasound attenuation, speed of sound or velocity of sound, and quantitative ultrasound index stiffness. Broadband ultrasound attenuation measures the frequency dependence of attenuation of the ultrasound signal that occurs as energy is removed from the wave, primarily by absorption and scattering in the bone and soft tissue (21). Speed of sound and velocity of sound measure the distance the ultrasound signal travels per unit of time (22). Quantitative ultrasound index and stiffness are composite parameters derived from broadband ultrasound attenuation and speed of sound or velocity of sound (21, 22). Ultrasound parameter values are typically lower in osteoporotic bone than in healthy bone (22). There are numerous calcaneal quantitative ultrasound devices in use, but there are no universal guidelines establishing normal versus abnormal measurement values. In addition, studies have reported correlation coefficient values between 0.44 and 0.93 for measurements of the same parameters by different quantitative ultrasound devices (23, 24). Several large prospective studies have shown that calcaneal quantitative ultrasound can predict future fracture risk nearly as well as DXA (25-28). Quantitative ultrasound also has several potential advantages over DXA: It is less expensive, is portable, does not involve ionizing radiation, and does not require specially trained personnel (29-32). Also, unlike DXA, quantitative ultrasound may be able to assess bone quality in addition to BMD (33-35). However, 2 key gaps in the evidence limit the use of quantitative ultrasound as a first-line diagnostic tool in clinical practice. First, there are no consensus diagnostic criteria for osteoporosis using this technique. The WHOs operational definition for osteoporosis was derived in the context of DXA and has typically been applied to DXA (36). Direct application of this definition to quantitative ultrasound is not advisable (37, 38). Second, clinical trials of the efficacy of medical therapies for reducing fracture risk in persons without a history of osteoporotic fracture have used DXA rather than quantitative ultrasound to select patients (39). It is not known whether the results of these trials can be generalized to patients identified by quantitative ultrasound as having high risk for fracture (39). Some evidence suggests that women selected for osteoporosis therapy on the basis of fracture risk factors rather than low DXA BMD may not benefit similarly from treatment (7). In the absence of direct evidence of treatment efficacy for patients identified by quantitative ultrasound as having high risk for fracture, the clinical utility of this test for improving osteoporosis outcomes lies with its degree of correlation with DXA results (40). Correlation coefficients between calcaneal quantitative ultrasound measurements and DXA BMD at the spine or the hip have ranged between 0.27 and 0.7 in several larger studies (41-51). Thus, several researchers have suggested that quantitative ultrasound could be used as a prescreening test to reduce the number of patients who require additional DXA testing (52-61). We performed a systematic review to address 3 questions relevant to such a strategy. First, what are the sensitivity and specificity of calcaneal quantitative ultrasound for identifying patients who meet WHO DXA osteoporosis criteria at the hip or the spine? Second, given a pretest probability of osteoporosis (for example, on the basis of risk factors, such as age and sex) and quantitative ultrasound results, what is the post-test probability of DXA-determined osteoporosis? Third, what do these findings tell us about the strength of the evidence supporting the use of calcaneal quantitative ultrasound to screen for osteoporosis? Methods Data Sources We searched MEDLINE (1966 to October 2005), EMBASE (1993 to May 2004), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (1952 to March 2004), and the Science Citation Index (1945 to April 2004) with assistance from a professional research librarian (Figure 1). We supplemented our searches by manually reviewing bibliographies of eligible studies and relevant review articles. Figure 1. Literature search strategies and reasons for study exclusion. Study Selection We included English-language studies that evaluated the sensitivity and specificity of calcaneal quantitative ultrasound for identifying adults with DXA T-scores of 2.5 or less at the hip or spine. We required that both sites be tested, with a T-score of 2.5 or less at either site indicative of osteoporosis (62, 63), because T-scores can differ at the lumbar spine and the hip (62-64) and the spine is often affected by bone loss earlier than the femoral neck. Thus, if only hip BMD was tested, some individuals at risk for vertebral fracture may have been missed. We chose to focus on studies with a DXA T-score of 2.5 or less as the reference standard because we felt this was the clinical population of most interest. Most of the randomized, controlled trials that have demonstrated efficacy of pharmacologic therapies for reducing fracture risk in persons without a history of fracture have done so in this population. In addition, several guidelines agree that persons with T-scores of 2.5 or less should be treated (65-67), although there is more controversy surrounding treatment of those without a history of fracture and T-scores greater than 2.5. We excluded studies that did not use DXA as the reference standard because the bulk of the evidence showing that medical therapy reduces fracture risk in persons without a history of osteoporotic fracture has been based on patient selection by DXA criteria. We limited inclusion to studies that performed quantitative ultrasound and DXA testing in all participants, had at least 10 participants with and 10 participants without DXA-determined osteoporosis, and reported at least 1 pair of sensitivity and specificity values (Figure 1). Data Extraction Two authors independently abstracted study design information, study participant information, results, and information about potential sources of bias from included studies (Appendix Table 1). We resolved abstraction discrepancies by repeated review and discussion. Appendix Table 1. Study Characteristics Data Synthesis All of the studies that met our inclusion criteria reported quantitative ultrasound thresholds (cutoff values used to separate positive results from negative results) corresponding to each pair of sensitivity and specificity values. We used this information to determine the relationship between threshold and sensitivity and specificity. We computed random-effects regression models with sensitivity or specificity as the dependent variable and threshold as the independent variable, as will be explained. We also calculated summary receiver-operating characteristic (ROC) curves using the sensitivity and specificity estimates reported by the included studies. We used MATLAB, version 7.0, release 14 (The MathWorks, Inc., Natick, Massachusetts), and STATA, version 8.1 (StataCorp LP, College Station, Texas), to perform our data an

Validation of FRC, a Fracture Risk Assessment Tool, in a Cohort of Older Men: The Osteoporotic Fractures in Men (MrOS) Study

OBJECTIVE We describe a girl with Cushing disease for whom surgery and radiation treatments failed and the subsequent clinical course with mifepristone therapy. METHODS We present the patients clinical, biochemical, and imaging findings. RESULTS A 16-year-old girl presented with classic Cushing disease. After transsphenoidal surgery, Cyberknife radiosurgery, ketoconazole, and metyrapone did not control her disease, and she was prescribed mifepristone, which was titrated to a maximal dosage of 1200 mg daily with subsequent symptom improvement. Mifepristone (RU486) is a high-affinity, nonselective antagonist of the glucocorticoid receptor. There is limited literature on its use as an off-label medication to treat refractory Cushing disease. Over her 8-year treatment with mifepristone, her therapy was complicated by hypertension and hypokalemia requiring spironolactone and potassium chloride. She received a 2-month drug holiday every 4 to 6 months to allow for withdrawal menstrual bleeding with medroxyprogesterone acetate. Urinary cortisol, serum cortisol, and corticotropin levels remained elevated during mifepristone drug holidays. While on mifepristone, her signs and symptoms of Cushing disease resolved. Repeated magnetic resonance imaging demonstrated stable appearance of the residual pituitary mass. Bilateral adrenalectomy was performed, and mifepristone was discontinued after 95 months of medical therapy. CONCLUSIONS We describe the longest duration of mifepristone therapy thus reported for the treatment of refractory Cushing disease. Mifepristone effectively controlled all signs and symptoms of hypercortisolism. Menstruating women who take the drug on a long-term basis should receive periodic drug holidays to allow for menses. The lack of reliable serum biomarkers to monitor the success of mifepristone therapy requires careful clinical judgment and may make its use difficult in Cushing disease.

Salivary cortisol increases after bariatric surgery in women.

We evaluated the performance of the Fracture Risk Calculator (FRC) in 5893 men who participated in the baseline visit (March 2000-April 2002) of the Osteoporotic Fractures in Men Study. FRC estimates for 10-yr hip and major osteoporotic (hip, clinical spine, forearm, and shoulder) fractures were calculated and compared with observed 10-yr fracture probabilities. Possible enhancement of the tools performance when bone mineral density (BMD) was included was evaluated by comparing areas under receiver operating characteristic curves and by Net Reclassification Improvement (NRI). A total of 5893 men were followed-up for an average of 8.4 yr. For most quintiles of predicted fracture risk, the ratios of observed to predicted probabilities were close to unity. Area under the curves improved when BMD was included (p<0.001; 0.79 vs 0.71 for hip fracture and 0.70 vs 0.66 for major osteoporotic fracture, respectively). Using National Osteoporosis Foundation clinical treatment thresholds, BMD inclusion increased NRI significantly, 8.5% (p<0.01) for hip and 4.0% (p=0.01) for major osteoporotic fracture. We conclude that the FRC calibrates well with hip and major osteoporotic fractures observed among older men. Further, addition of BMD to the fracture risk calculation improves the tools performance.

Systematic Review: The Safety and Efficacy of Growth Hormone in the Healthy Elderly

Cortisol increases have been associated with psychological and physiological stress; however, cortisol dynamics after weight loss (bariatric) surgery have not been defined. Obese participants not using exogenous glucocorticoids were eligible to participate. Female participants (n=24) provided salivary cortisol samples at bedtime, upon awakening the following morning, and 30 min after awakening before, and at 6 or 12 months after bariatric surgery. The Medical Outcomes Study Short Form-12 version 2 questionnaire regarding health-related quality of life was also completed. Preoperatively, mean body mass index was 45.1±8.1 kg/m2. Mean late night (1.8±1.1 nmol/l), awakening (10.7±7.4 nmol/l), and after-awakening (11.5±7.9 nmol/l) salivary cortisol values were within normal ranges. The cortisol awakening response (mean 21.1±79.7%, median 13.7%) was at the low end of normal. Preoperatively, participants had lower mental and physical health-related quality of life scores than US adult norms (p<0.001). Salivary cortisol was not correlated with measures of health-related quality of life. Mean BMI decreased over time (p<0.001) and participants experienced improved physical and mental health-related quality of life (p≤0.011). Postoperative late night salivary cortisol was not different from preoperative values. Awakening and after-awakening cortisol levels were higher than preoperative values (15.3±7.7 nmol/l, p=0.013; 17.5±10.2 nmol/l, p=0.005; respectively), but the cortisol awakening response was not changed (mean 26.7±66.2%; median 7.8%). Morning salivary cortisol increased at long-term follow-up after bariatric surgery. Although self-evaluated mental and physical health improved after surgery, the cortisol awakening response is at the low end of normal, which may indicate continued physiological stress.