Jeffrey L. Jackson

Predictors of patient satisfaction

Correlates of patient satisfaction at varying points in time were assessed using a survey with 2-week and 3-month follow-up in a general medicine walk-in clinic, in USA. Five hundred adults presenting with a physical symptom, seen by one of 38 participating clinicians were surveyed and the following measurements were taken into account: patient symptom characteristics, symptom-related expectations, functional status (Medical Outcomes Study Short-Form Health Survey [SF-6]), mental disorders (PRIME-MD), symptom resolution, unmet expectations, satisfaction (RAND 9-item survey), visit costs and health utilization. Physician perception of difficulty (Difficult Doctor Patient Relationship Questionnaire), and Physician Belief Scale. Immediately after the visit, 260 (52%) patients were fully satisfied with their care, increasing to 59% at 2 weeks and 63% by 3 months. Patients older than 65 and those with better functional status were more likely to be satisfied. At all time points, the presence of unmet expectations markedly decreased satisfaction: immediately post-visit (OR: 0.14, 95% CI: 0.07-0.30), 2-week (OR: 0.07, 95% CI: 0.04-0.13) and 3-month (OR: 0.05, 95% CI: 0.03-0.09). Other independent variables predicting immediate after visit satisfaction included receiving an explanation of the likely cause as well as expected duration of the presenting symptom. At 2 weeks and 3 months, experiencing symptomatic improvement increased satisfaction while additional visits (actual or anticipated) for the same symptom decreased satisfaction. A lack of unmet expectations was a powerful predictor of satisfaction at all time-points. Immediately post-visit, other predictors of satisfaction reflected aspects of patient doctor communication (receiving an explanation of the symptom cause, likely duration, lack of unmet expectations), while 2-week and 3-month satisfaction reflected aspects of symptom outcome (symptom resolution, need for repeat visits, functional status). Patient satisfaction surveys need to carefully consider the sampling time frame as well as adjust for pertinent patient characteristics.

Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis.

BACKGROUND Functional gastrointestinal disorders are common, accounting for up to 50% of gastroenterology referrals, and several randomized controlled trials have evaluated antidepressant therapy for their treatment. METHODS We performed a meta-analysis of published, English-language, randomized clinical trials on the use of antidepressants for the treatment of patients with functional gastrointestinal disorders. RESULTS Twelve randomized placebo-controlled trials of antidepressant treatment of functional gastrointestinal disorders were identified. One was excluded for using a combination of a tricyclic and neuroleptic agent. The medications included tricyclic antidepressants (amitriptyline [n = 3], clomipramine [n = 1], desipramine [n = 2], doxepin [n = 1], and trimipramine [n = 2]), and the antiserotonin agent, mianserin (n = 2). In addition, one trial compared two different antidepressants (mianserin and clomipramine) with placebo. Data were abstracted for the dichotomous outcome of symptom improvement in seven studies, and for the continuous variable of pain score in eight studies. The summary odds ratio for improvement with antidepressant therapy was 4.2 (95% confidence interval [CI]: 2.3 to 7.9), and the average standardized mean improvement in pain was equal to 0.9 SD units (95% CI: 0.6 to 1.2 SD units). On average 3.2 patients needed to be treated (95% CI: 2.1 to 6.5 patients) to improve 1 patients symptom. CONCLUSION Treatment of functional gastrointestinal disorders with antidepressants appears to be effective. Whether this improvement is independent of an effect of treatment on depression needs further evaluation.

Meta-analysis : Computed tomographic colonography

Colorectal cancer is the second most frequent cause of cancer-related death in the United States. Nearly 150000 new cases and 60000 deaths occur each year from this disease (1). Because colorectal cancer develops insidiously over time as genetic mutations accumulate in clinically silent adenomatous polyps, it is most commonly diagnosed at an advanced stage (2-4). If the condition is diagnosed at an early stage, the prognosis is favorable, with 5-year survival rates exceeding 90% (5, 6). Colorectal cancer, unlike many other types of cancer, can be prevented by removal of precancerous lesions. The long preclinical phase, early detectability, and improved prognosis of colorectal cancer have established the need for an accurate screening method. Various screening tests in current use reduce the incidence and rate of death from colorectal cancer (7, 8). Despite the proven efficacy of these tests, however, patient adherence to screening guidelines is low: Only 30% to 45% of persons eligible for screening undergo such tests. Low adherence rates are believed to be due to poor public awareness and poor public acceptance of current screening techniques (9-13). An increasingly popular screening test for colorectal cancer is computed tomographic (CT) colonography, also known as CT colography or virtual colonoscopy. Computed tomographic colonography was first described in 1994 as a radiographic technique in which thin-section images of pneumocolon could be reconstructed by sophisticated software into high-resolution 2- and 3-dimensional images (14). Over time, improvements in hardware and software have allowed faster scanning, reduced exposure to radiation, and better imaging. Newer modes of imaging (called fly-through) can produce results that resemble endoscopic images and permit sophisticated characterization of detected lesions (15-17). Early studies primarily used the spiral CT scanner, which has limitations in spatial resolution that can make small polyps more difficult to detect (17). The multidetector CT scanner has permitted rapid acquisition of finer images, obtained during a single breath-hold, that can greatly improve image quality and spatial resolution (17, 18). Many aspects of this technology are under study, including software that assists in detection of lesions, refinements in image reconstruction, and stool tagging (19-21). The latter development relies on ingestion of contrast material over several days or hours, after which software digitally subtracts residual solid and fluid fecal material from the acquired images, creating a virtually clean mucosal surface (22, 23). This technique may improve sensitivity and may someday obviate the need for bowel cleansing before examination. Although it is touted as a less invasive screening method than flexible sigmoidoscopy or colonoscopy, CT colonography typically requires full bowel cleansing and insufflation of air through the rectum (24). Studies have suggested that CT colonography may be similar, and in some cases preferable, to colonoscopy in terms of comfort and acceptability, but no convincing difference between these 2 approaches has been demonstrated (25-31). If virtual colonoscopy is found to have equivalent test characteristics, improve patient adherence, and be safer or less expensive than colonoscopy, it may be more cost-effective and become the screening method of choice (32, 33). Studies of the test characteristics of CT colonography have had mixed results. Pickhardt and colleagues used CT colonography in 1233 patients and found a sensitivity of 93.9% for adenomatous polyps larger than 8 mm (25). Other studies have had less favorable results, with sensitivities as low as 55% for polyps larger than 10 mm, raising concerns about the overall test performance of CT colonography when used in a broader range of settings (34). Various reasons for these discrepant results have been offered, but the source of this heterogeneity has not been fully explored (16, 35, 36). Such assessment is needed because patients and providers look to this technology in the hope of improving screening rates (29). We systematically reviewed the literature to assess the test performance of CT colonography compared with colonoscopy or surgery, to define characteristics of these studies, and to attempt to explain the sources of conflicting results. Methods Study Identification and Selection We searched the PubMed, EMBASE, and MEDLINE databases and the Cochrane Controlled Trials Register for all relevant articles published in the English language between 1975 and February 2005 by using the Medical Subject Headings or text words virtual colonoscopy, CT colonography, CT colography, or CT pneumocolon. The title and abstract of potentially relevant studies and review articles were screened for appropriateness before retrieval of the full articles. Two reviewers independently searched the literature. Inclusion criteria were a prospective, blinded design (in which results of CT colonography were interpreted independently of findings on colonoscopy or during surgery); enrollment of adult patients who were to undergo CT colonography after a full bowel preparation, followed by complete colonoscopy or surgery; and use of at least a single-detector CT scanner, with colon insufflation by air or carbon dioxide, scan intervals no greater than 5 mm, and use of both 2-dimensional and 3-dimensional views during scan interpretation. Study Quality Two observers independently extracted data on test characteristics; study setting; patients; and components of methodologic quality that may be associated with bias in test accuracy studies, including disease severity, disease prevalence, prospective design, relevant clinical sample (as opposed to a diagnostic casecontrol study), enrollment of a series of consecutive patients, assurance that all patients underwent reference testing, performance and interpretation of the index test without knowledge of the results of the reference test, and performance and interpretation of the reference test without knowledge of the results of the index test (33). A piloted standardized data extraction sheet was used, and disagreements were resolved by consensus. Data Abstraction We abstracted characteristics of the study (design, country, year, reference standard, and type of contrast used), patients (demographic and risk for colorectal cancer), scanners (manufacturer, type of viewer, type of contrast, software, and hardware), and study quality. Sensitivity and specificity were calculated per patient, per polyp, and for polyps of 3 size categories: smaller than 6 mm, 6 to 9 mm, and larger than 9 mm. When data on test performance were reported for 2 or more separate CT colonography readers, we calculated an average value. When possible, we excluded data on double readings. If a study reported data related specifically to adenomas instead of polyps, in general, we abstracted only the data for adenomas. For studies that performed retrospective analysis (for example, fly-through imaging in the study by Cotton and associates [34]), we abstracted only data on CT colonography findings before colonoscopy. If data could not be extracted or calculated from the manuscript with confidence, none were entered. Two reviewers independently abstracted data, and disagreements were resolved by consensus. Statistical Analysis Pooled sensitivities and specificities on a per-patient basis were combined and weighted according to sample size. Confidence intervals for each study were calculated by using exact binomial methods in a random-effects model. We focused our analysis on per-patient data because this is the most important perspective for a screening test, whereas per-polyp data emphasize the ability of CT colonography to find colonic lesions. That is, the latter analysis assesses the performance of the technology rather than its utility as a screening tool. Heterogeneity was assessed by using the I2 statistic (37). The I2 statistic provides an estimate of the amount of variance due to heterogeneity rather than chance and is based on the traditional measure of variance, the Cochrane Q statistic. Potential threshold effects were assessed by using the Spearman statistic and by creating receiver-operating characteristic curves according to the method of Moses and coworkers (38). Heterogeneity was assessed by performing stratified analyses when the potential confounding variable was dichotomous or categorical, by plotting the weighted effect size against the potential confounding variable when that variable was continuous, and by applying meta-regression methods in either case (39). Subgroup analyses were done by year of publication, imaging technique (2-dimensional imaging with 3-dimensional confirmation only when a lesion was noted, 3-dimensional imaging with 2-dimensional confirmation, 2-dimensional imaging with concomitant 3-dimensional imaging, or fly-through technology), collimation width and reconstruction interval (in millimeters), type of scanner (single-detector, multidetector, or mixed), and use of a contrast agent (yes or no). When collimation or reconstruction thickness was given in half-millimeter increments, we rounded the values up to the next whole number. The meta-regression analysis used the restricted maximum likelihood method and was performed by using indicator variables to assess differences among the strata. All analyses were performed with Stata software, version 8.2 (Stata Corp., College Station, Texas). Data Synthesis Our final pool of eligible studies (Appendix Figure) included 33 prospective studies involving 6393 patients that compared CT colonography to the reference standard of colonoscopy or surgery (22, 25, 34, 40-69). Studies originated from 7 different countries, but most were done in the United States (64%). The average number of participants in a study was 248 (range, 20 to 1233). The mean age of participants was 61.9 years; 63.6% of participants were ma

Treatment of Fibromyalgia with Antidepressants: A Meta-analysis

AbstractBACKGROUND: Fibromyalgia is a common, poorly understood musculoskeletal pain syndrome with limited therapeutic options. OBJECTIVE: To systematically review the efficacy of antidepressants in the treatment of fibromyalgia and examine whether this effect was independent of depression. DESIGN: Meta-analysis of English-language, randomized, placebo-controlled trials. Studies were obtained from searching medline, embase, and psyclit (1966-1999), the Cochrane Library, unpublished literature, and bibliographies. We performed independent duplicate review of each study for both inclusion and data extraction. MAIN RESULTS: Sixteen randomized, placebo-controlled trials were identified, of which 13 were appropriate for data extraction. There were 3 classes of antidepressants evaluated: tricyclics (9 trials), selective serotonin reuptake inhibitors (3 trials), and S-adenosylmethionine (2 trials). Overall, the quality of the studies was good (mean score 5.6, scale 0–8). The odds ratio for improvement with therapy was 4.2 (95% confidence interval [95% CI], 2.6 to 6.8). The pooled risk difference for these studies was 0.25 (95% CI, 0.16 to 0.34), which calculates to 4 (95% CI, 2.9 to 6.3) individuals needing treatment for 1 patient to experience symptom improvement. When the effect on individual symptoms was combined, anti-depressants improved sleep, fatigue, pain, and well-being, but not trigger points. In the 5 studies where there was adequate assessment for an effect independent of depression, only 1 study found a correlation between symptom improvement and depression scores. Outcomes were not affected by class of agent or quality score using meta-regression. CONCLUSION: Antidepressants are efficacious in treating many of the symptoms of fibromyalgia. Patients were more than 4 times as likely to report overall improvement, and reported moderate reductions in individual symptoms, particularly pain. Whether this effect is independent of depression needs further study.

Depressive and Anxiety Disorders in Patients Presenting With Physical Complaints: Clinical Predictors and Outcome

PURPOSE To identify the predictors of depressive and anxiety disorders in general medical patients presenting with physical complaints and to determine the effect of these mental disorders on patient outcome. PATIENTS AND METHODS In this cohort study, 500 adults presenting to a general medicine clinic with a chief complaint of a physical symptom were interviewed with PRIME-MD to diagnose DSM-IV depressive and anxiety disorders. Clinical predictors were identified by logistic regression analysis. Outcomes were assessed immediately postvisit and at 2 weeks and 3 months. These included symptomatic improvement, functional status, unmet expectations, satisfaction with care, clinician-perceived patient difficulty, and health care utilization and costs. RESULTS A depressive or anxiety disorder was present in 146 (29%) of the patients. Independent predictors of a mental disorder included recent stress, multiple physical symptoms (ie, 6 or more), higher patient ratings of symptom severity, lower patient ratings of their overall health, physician perception of the encounter as difficult, and patient age less than 50. Patients with depressive or anxiety disorders were more likely to have unmet expectations postvisit (20% versus 8%, P < 0.001), be considered difficult (26% versus 11%, P < 0.0001), and report persistent psychiatric symptoms and ongoing stress even 3 months following the initial visit. Psychiatric status was not associated with symptomatic improvement, health care utilization, or costs. CONCLUSION Simple clinical clues in patients with physical complaints identify a subgroup who may warrant further evaluation for a depressive or anxiety disorder. Such disorders are associated with unmet patient expectations and increased provider frustration.

Meta-analysis : The effect of statins on albuminuria

Context Albuminuria is a marker of endothelial dysfunction and is a risk factor for cardiovascular disease. We do not know whether or to what degree statins affect albuminuria. Contribution This meta-analysis of 15 randomized, placebo-controlled trials found that statins reduced albuminuria and proteinuria. Studies with greater baseline albuminuria showed greater reductions. Cautions Studies were small, showed heterogeneous effects, and were often of poor quality. Implications Statins might reduce albuminuria. We need larger, better studies to confirm these findings and to determine whether reducing albuminuria affects the incidence of end-stage renal disease or cardiovascular disease. The Editors Amarker of endothelial dysfunction, albuminuria has long been recognized as a risk factor for progression to end-stage renal disease. More recently, however, albuminuria has been recognized as an independent risk factor for cardiovascular morbidity and mortality (14). Beyond angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapies, therapeutic options to affect the progression of albuminuria are limited. One therapeutic option may be 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). The beneficial effects of statins on cardiovascular morbidity and mortality cannot be explained solely by their effect on low-density lipoprotein (LDL) cholesterol levels (57) and may involve an independent effect on endothelial dysfunction. Some investigators have noted that the effects of statins exceed those expected from simply lowering LDL cholesterol levels and occur too early in treatment to be due to the lowering of LDL cholesterol levels (8). The nonlipid mechanisms that may be involved are called pleiotropic effects, such as lipid-independent plaque stabilization, reduced inflammation, decreased thrombogenicity, increased arterial compliance, and improved endothelial function (7, 912). We systematically reviewed the literature to determine whether and to what degree statins affect albuminuria or proteinuria. Methods Literature Search We searched the PubMed, MEDLINE, EMBASE, BIOSIS, SciSearch, PASCAL, and International Pharmaceutical Abstracts (IPA) databases, as well as the Cochrane Central Register of Controlled Trials, for all relevant articles published in any language between January 1974 and November 2005. We used the following Medical Subject Headings (MeSH) and text words: proteinuria, urinary protein excretion, albuminuria, urinary albumin excretion, pitavastatin, mevastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, lovastatin, and rosuvastatin. We limited our searches to randomized, placebo-controlled trials in adults (age >18 years). Study Selection Two investigators independently screened the titles and abstracts of potentially relevant studies before retrieving the full-text articles. When investigators doubted a studys eligibility for inclusion, they obtained the full-text article. We included randomized, controlled trials that studied adults and had both a statin group and a placebo group. We considered the end point to be appropriate if proteinuria or albuminuria was measured either by timed urine collections to measure 24-hour excretion or by untimed specimens to calculate albumin-to-creatinine ratios. We complemented the database searches by reviewing the a priori end points of major lipid-lowering trials and the reference lists from original research articles, review articles, and previous meta-analyses. We focused exclusively on published data and did not contact authors of trials that met selection criteria but did not have data on albuminuria or proteinuria. Validity Assessment Two reviewers independently assessed study quality by using the Jadad rating instrument (13), complemented by an assessment of the intention-to-treat analysis, loss to follow-up, and industry sponsorship. Jadad scores are based on the description of randomization, blinding, inclusion and exclusion criteria, withdrawals, and method to assess adverse events. Scores can range from 0 to 8, and higher scores indicate better methodologic quality. We calculated interrater agreement, and we resolved differences by consensus. Data Extraction We extracted characteristics of the study (author, year, country, design, duration, statin and dosage, and sample size) and the participants (age, sex, presence and type of renal disease, proportion with diabetes, proportion with hypertension, baseline and follow-up cholesterol levels, baseline and follow-up urinary albumin and protein excretion rates, angiotensin-converting enzyme inhibitor use, angiotensin II receptor blocker use, and calcium-channel blocker use). If data could not be extracted or calculated from the manuscript with confidence, no data were entered. Two reviewers independently extracted data, and we resolved disagreements by consensus. Quantitative Data Synthesis The principal measure of effect was the weighted mean difference in the proportional change from baseline to follow-up albuminuria (or proteinuria) between the statin and placebo groups. We pooled the results by using a random-effects model to obtain the summary weighted mean difference with confidence interval. To avoid bias from carryover effects, we used data from only the first phase of crossover studies for the analysis when possible. We replaced missing means with the reported medians for calculating the weighted mean difference. We imputed missing SDs on the basis of reported P values, if available. We performed these imputations conservatively to err on the side of underestimating the statistical significance of positive studies. Specifically, we approximated imputed values to just reach statistical significance (for example, if the reported P value was less than 0.050, we imputed a value that would yield a P value of 0.049). When P values were not available, we imputed the SDs by using the mean proportional SD of the other studies. Both baseline and follow-up SDs were weighted by sample size and were averaged before inclusion in the random-effects model. We conducted sensitivity analyses for the imputed values. We assessed heterogeneity by using the I2 statistic (14). The I2 statistic is an estimate of the amount of variance due to heterogeneity rather than chance and is based on the traditional measure of variance, the Cochran Q statistic. We assessed the sources of heterogeneity by performing stratified analyses (15). We considered a P value less than 0.050 to indicate statistically significant heterogeneity. We performed 2 subgroup analyses for the variables that we deemed most likely to be the potential sources of statistical heterogeneity and for which data were complete. These variables included the baseline level of urinary excretion (calculated as the weighted average of statin and placebo group data and reflecting the presence and severity of disease and the likelihood of benefit from therapy) and loss to follow-up (the quality measure exhibiting the most variation across studies). The cut-points used for urinary excretion level were less than 30 mg/d (n= 3), corresponding to nonpathologic levels; 30 to 299 mg/d (n= 6), corresponding to microalbuminuric levels; and 300 mg/d or greater (n= 6), corresponding to macroalbuminuric levels. For losses to follow-up, we used cut-points of more than 20% (n= 3) and 5% or less (n= 12), which may represent excessive and minimal bias, respectively. Publication Bias We assessed publication bias by using the Begg method with funnel plot analysis (16). Sensitivity Analyses To exclude the possibility that any one study was exerting excessive influence on the results, we conducted a sensitivity analysis by systematically excluding each study and then reanalyzing the data to assess the change in effect size. In addition, because gross proteinuria might reflect tubular dysfunction rather than endothelial glomerular dysfunction, we conducted a sensitivity analysis by excluding the 4 studies that measured only gross proteinuria. We performed all analyses with Stata software, version 8.2 (Stata Corp., College Station, Texas). We considered P values less than 0.050 to be statistically significant. We used the Quality of Reports of Meta-analyses (QUOROM) statement to guide both our reporting and our discussion of the results of our meta-analysis (17). Role of the Funding Source No funding was received in support of our study. Results Literature Search Figure 1 shows the literature search and selection flow chart. Figure 1. Study flow diagram. Study and Patient Characteristics Our final pool of eligible studies included 15 randomized, placebo-controlled trials involving 1384 participants (1832). Studies originated from 10 different countries. Most studies were performed in Europe (53%), and only 1 study was performed in the United States. All studies measured the outcome by using a 24-hour urine collection. Three studies enrolled participants with normal albumin excretion (<30 mg/d), 6 studies enrolled participants with microalbuminuria (30 to 299 mg/d), and 6 studies enrolled participants with gross albuminuria (n= 2) or proteinuria (n= 4) (300 mg/d). The median number of participants in each study was 36 (range, 18 to 864 participants). Statins were (in order of decreasing frequency) simvastatin (5 studies), pravastatin (4 studies), fluvastatin and cerivastatin (2 studies each), and atorvastatin and lovastatin (1 study each). The median reduction in LDL cholesterol level was 26% (range, 10% to 51%). Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were used concurrently in 7 studies and were prohibited in 4 studies. We could not determine their use for the remaining 4 studies. Except for 1 study (26), which measured albuminuria as a potential adverse event, all studies measured either albuminuria (n= 10) or proteinuria (n= 4) as an a priori efficacy outcome. The median duration of f

Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment?

Context Studies of Spanish influenza that evaluated effects of transfusion with influenza-convalescent blood products might offer insights regarding potential treatments for H5N1 influenza. Contribution This review of 8 controlled studies published in English-language medical literature between 1918 to 1925 found that transfusion with influenza-convalescent human blood products may have reduced risk for death in hospitalized patients with Spanish influenza complicated by pneumonia. Transfusions caused some chill reactions. Cautions Studies had many methodologic limitations. Implications Studies from the Spanish influenza era support the idea that convalescent human H5N1 plasma could be an effective, accessible treatment that should be studied in clinical trials. The Editors The world is bracing for a potential H5N1 influenza pandemic. During the Spanish influenza pandemic, an estimated 30% of the worlds population became ill and 50 million people died (1). An H5N1 influenza pandemic could be equally or more severe. Unfortunately, effective vaccines will be difficult to produce before a novel human pandemic strain emerges and will take substantial time to manufacture and distribute in quantity. It is sobering that the worlds annual production capacity for influenza vaccine is 300 million doses (2)enough for 4.5% of the worlds population. These facts have caused some governments to develop response plans to pandemic influenza that involve creating antiviral stockpiles and increasing the capacity to handle surges in the need for medical care. Patients with H5N1 influenza often develop a fatal case of acute respiratory distress syndrome or multiple organ dysfunction syndrome that is similar to the syndromes reported in patients with Spanish influenza who developed pneumonia-like complications (35). To treat patients with H5N1 influenza, the World Health Organization recommends hospitalization with early use of oseltamivir and supportive care (3). Despite these treatments, 30% to 80% of hospitalized patients with H5N1 influenza have died, and an oseltamivir-resistant virus has developed in some patients (3, 4). A case series report of Vietnamese patients with H5N1 influenza suggested that supportive care may be the only option available (4). Even if more effective standard pharmaceutical treatments are produced, it is unlikely that sufficient quantities will be rapidly or widely available because of financial, logistical, and health care delivery limitations. Passively delivered anti-influenza antibodies in convalescent human plasma obtained from H5N1 survivors may offer a novel treatment approach and possible solution to these problems. Passive antibodies have been used to prevent or treat such diseases as rabies, measles, hepatitis B, cytomegalovirus, and respiratory syncytial virus (6), and convalescent human plasma may have efficacy in the treatment of severe acute respiratory syndrome (7, 8). The modern plasmapheresis systems in many hospitals and blood collection centers currently produce large volumes of plasma for treating coagulopathies and other conditions (9, 10). The same infrastructure, personnel, and regulatory framework could produce convalescent plasma for the treatment of H5N1 influenza. To help assess the potential treatment efficacy of convalescent plasma in reducing mortality in current patients with H5N1 influenza, we conducted a review of studies from the Spanish influenza era that used influenza-convalescent human blood products to treat patients with Spanish influenza complicated by pneumonia (influenza pneumonia). Methods Data Sources and Searches We developed and followed a protocol for the literature review and also followed standard reporting guidelines (11). The medical literature during the 1920s was not centrally indexed in an electronic or text database. Two authors first conducted a preliminary survey and study of the original medical literature published about Spanish influenza. This was done to gain an understanding of the scientific concepts, research methods, medical practices, and vocabulary used during that era to aid in the development of our review and search strategy. Subsequently, 1 author conducted a manual review of the indexes of the following medical journals from 1918 to 1925: Journal of the American Medical Association, Boston Medical and Surgical Journal (now New England Journal of Medicine), British Medical Journal, Canadian Medical Association Journal, Lancet, Archives of Internal Medicine, The Military Surgeon (United States), and Naval Medical Bulletin (United States). We searched 3 terms in the journal indexes: influenza, serotherapy, and pneumonia. We then searched subindexes or article titles that were listed under the 3 categories for any of the following terms: influenza, serotherapy, pneumonia, serum, plasma, blood, bronchopneumonia, convalescent, intravenous, and transfusion. Potentially relevant articles were obtained and reviewed. We also reviewed references of relevant articles. Of note, many of the source journals provided an indexed abstract section of articles drawn from other English-language and nonEnglish-language journals. Original articles on our topic were often published as an abstract by other journals, and the articles often cross-referenced each other. For practical reasons, including feasibility and resource constraints, we limited our searches to years in which relevant studies were likely to be published. Study Selection Two authors selected studies published in an English-language medical journal that met inclusion criteria defined a priori (Figure 1). Studies had to have used convalescent whole blood, plasma, or serum obtained from humans who had recovered from Spanish influenza as the treatment product and had to indicate the type, route, and volume of the product that was used. The treatment and control groups had to have included hospitalized patients with a diagnosis of influenza complicated by pneumonia, and investigators had to report mortality rates. The treatment group had to include at least 10 patients. The control group had to receive standard care and could not be assigned to receive, as a group, an alternative experimental therapy, such as an equine-derived antipneumococcus serum. Studies had to be conducted in a hospital setting during the Spanish influenza pandemic of 1918 to 1920. We excluded studies if they were reported only as an editorial, commentary, or abstract or as a translated synopsis of a nonEnglish-language study. Figure 1. Flow diagram of trial identification and selection. *Most of these studies were excluded on the basis of multiple criteria. Our rationale for the detailed inclusion and exclusion criteria was as follows. Hospitalized patients were likely to have had very severe illness and a more reliable diagnosis of influenza pneumonia than were patients whose illness was diagnosed and treated by general practitioners in the home. Although strains of Spanish influenza probably circulated before 1918 and certainly did so after 1920, the accuracy of a diagnosis of Spanish influenza pneumonia was likely to be reasonably good during years when herd immunity was low, the virus was virulent, and large epidemics occurred. Because scientific concepts, research methods, medical practices, and vocabulary have changed markedly since 1920, we restricted our analysis to articles that we could carefully scrutinize and for which we could reasonably reliably determine the primary clinical condition of patients, the treatment that was given, and characteristics of the treatment and control groups. Data Extraction and Quality Assessment Two authors independently extracted data about study characteristics, outcomes, adverse events, and quality. Disagreements were resolved by consensus. The quality of each study was assessed by using a 27-item checklist that was developed to assess the methodologic quality of randomized and nonrandomized studies of health care interventions (12). The quality scores could range from 0 to 27, with higher scores indicating better quality. Data Synthesis and Analysis We used as the principal measure of effect the range of absolute risk differences in death between the treatment and control groups. We conducted a planned subgroup analysis of mortality among patients who received early treatment (after <4 days of illness) compared with those who received late treatment (after 4 days). We also calculated overall crude case-fatality rates and pooled absolute risk differences in death by using the random-effects model of DerSimonian and Laird (13). Heterogeneity was assessed visually by using Galbraith plots (14) and statistically by using the I 2 statistic (15). To exclude the possibility that any one study was excessively influencing the results, we conducted a sensitivity analysis by excluding each study one at a time. We used the method of Egger and colleagues (16) to assess for statistical evidence of possible publication bias. All analyses were performed by using Stata software, version 9.1 (Stata Corp., College Station, Texas). Role of the Funding Source No funding was received for this review. Results Study Selection and Evaluation We searched hundreds of titles in the topic indexes and retrieved 72 manuscripts for screening (Figure 1). Many of these studies focused on the isolation and identification of the influenza bacillus or known bacterial pathogens or used various animal-derived antipneumococcus serums or other preparations for treatment. In 27 reports, influenza-convalescent human blood products were used to treat patients with Spanish influenza, with or without pneumonia complications. Of these, 8 studies described in 10 reports met all of our inclusion criteria (1726). No included study was identified solely from the citation review. We excluded 17 articles that were small case reports, were incomplete or noninterpretable, were written in a non-English language, or involved o

Association Between Alcohol Consumption and Both Osteoporotic Fracture and Bone Density

OBJECTIVE Alcoholism is a risk factor for osteoporotic fractures and low bone density, but the effects of moderate alcohol consumption on bone are unknown. We performed a systematic review and meta-analysis to assess the associations between alcohol consumption and osteoporotic fractures, bone density and bone density loss over time, bone response to estrogen replacement, and bone remodeling. METHODS MEDLINE, Current Contents, PsychINFO, and Cochrane Libraries were searched for studies published before May 14, 2007. We assessed quality using the internal validity criteria of the US Preventive Services Task Force. RESULTS We pooled effect sizes for 2 specific outcomes (hip fracture and bone density) and synthesized data qualitatively for 4 outcomes (non-hip fracture, bone density loss over time, bone response to estrogen replacement, and bone remodeling). Compared with abstainers, persons consuming from more than 0.5 to 1.0 drinks per day had lower hip fracture risk (relative risk=0.80 [95% confidence interval, 0.71-0.91]), and persons consuming more than 2 drinks per day had higher risk (relative risk=1.39 [95% confidence interval, 1.08-1.79]). A linear relationship existed between femoral neck bone density and alcohol consumption. Because studies often combined moderate and heavier drinkers in a single category, we could not assess relative associations between alcohol consumption and bone density in moderate compared with heavy drinkers. CONCLUSION Compared with abstainers and heavier drinkers, persons who consume 0.5 to 1.0 drink per day have a lower risk of hip fracture. Although available evidence suggests a favorable effect of alcohol consumption on bone density, a precise range of beneficial alcohol consumption cannot be determined.

Botulinum Toxin A for Prophylactic Treatment of Migraine and Tension Headaches in Adults: A Meta-analysis

CONTEXT Botulinum toxin A is US Food and Drug Administration approved for prophylactic treatment for chronic migraines. OBJECTIVE To assess botulinum toxin A for the prophylactic treatment of headaches in adults. DATA SOURCES A search of MEDLINE, EMBASE, bibliographies of published systematic reviews, and the Cochrane trial registries between 1966 and March 15, 2012. Inclusion and exclusion criteria of each study were reviewed. Headaches were categorized as episodic (<15 headaches per month) or chronic (≥15 headaches per month) migraine and episodic or chronic daily or tension headaches. STUDY SELECTION Randomized controlled trials comparing botulinum toxin A with placebo or other interventions for headaches among adults. DATA EXTRACTION Data were abstracted and quality assessed independently by 2 reviewers. Outcomes were pooled using a random-effects model. DATA SYNTHESIS Pooled analyses suggested that botulinum toxin A was associated with fewer headaches per month among patients with chronic daily headaches (1115 patients, -2.06 headaches per month; 95% CI, -3.56 to -0.56; 3 studies) and among patients with chronic migraine headaches (n = 1508, -2.30 headaches per month; 95% CI, -3.66 to -0.94; 5 studies). There was no significant association between use of botulinum toxin A and reduction in the number of episodic migraine (n = 1838, 0.05 headaches per month; 95% CI, -0.26 to 0.36; 9 studies) or chronic tension-type headaches (n = 675, -1.43 headaches per month; 95% CI, -3.13 to 0.27; 7 studies). In single trials, botulinum toxin A was not associated with fewer migraine headaches per month vs valproate (standardized mean difference [SMD], -0.20; 95% CI, -0.91 to 0.31), topiramate (SMD, 0.20; 95% CI, -0.36 to 0.76), or amitriptyline (SMD, 0.29; 95% CI, -0.17 to 0.76). Botulinum toxin A was associated with fewer chronic tension-type headaches per month vs methylprednisolone injections (SMD, -2.5; 95% CI, -3.5 to -1.5). Compared with placebo, botulinum toxin A was associated with a greater frequency of blepharoptosis, skin tightness, paresthesias, neck stiffness, muscle weakness, and neck pain. CONCLUSION Botulinum toxin A compared with placebo was associated with a small to modest benefit for chronic daily headaches and chronic migraines but was not associated with fewer episodic migraine or chronic tension-type headaches per month.

Meta-analysis: outcomes in patients with suspected pulmonary embolism managed with computed tomographic pulmonary angiography.

Context Is it safe to withhold anticoagulation in adults with suspected pulmonary embolism (PE) and negative results on spiral computed tomographic pulmonary angiography (CTPA)? Contribution This meta-analysis summarized data from 23 studies that reported rates of thromboembolism among patients with suspected PE who did not receive anticoagulation after negative results on CTPA. Among 4657 patients, the 3-month risks for a thromboembolic event and fatal PE were 1.4% and 0.51%, respectively. Cautions Studies used early-generation CT technology and different diagnostic algorithms for thromboembolism. Implications Withholding anticoagulation from patients with low to moderate probability of PE and negative results on CTPA appears reasonable. The Editors Pulmonary embolism (PE) remains a major cause of morbidity and mortality (1). The limitations of clinical examination in establishing a diagnosis of PE, as well as the perils of unnecessary anticoagulation and untreated clots, mandate use of judicious objective diagnostic testing in the evaluation of this disorder. Spiral computed tomographic pulmonary angiography (CTPA) has become an integral part of the diagnostic evaluation for suspected PE, given its widespread availability, ease of acquisition, favorable performance characteristics (2), and utility in revealing alternative diagnoses (3, 4). Researchers have been cautiously optimistic that CTPA may be useful as a definitive study to exclude PE (5). However, CTPA is often applied as part of an algorithmic screening approach that includes other diagnostic tests, including pretest prediction models, d-dimer testing, lower-extremity compression ultrasonography, and lung scintigraphy (3, 6-13). Many of these algorithms recommend conventional pulmonary angiography (CPA) as the gold standard (14). Although screening algorithms are reported to have good efficacy, they remain cumbersome to apply (15) and may be considerably underused in clinical practice (16). Some recent investigations suggest that CTPA merits consideration as a definitive diagnostic study (17-19). However, many authors remain unconvinced that negative CTPA results alone can reliably exclude clinically significant pulmonary emboli (20, 21). Bates and Ginsberg (20) have proposed that acceptance of CTPA as a definitive study would require establishment of its interobserver and intraobserver variability and study characteristics, determination of its accuracy, and an assessment of outcomes after anticoagulation is withheld because of a negative test result. The first 2 criteria have been evaluated (21, 22). In the current study, we performed a systematic review of the literature and conducted a meta-analysis of eligible studies to determine the safety and efficacy of withholding systemic anticoagulation after negative results on CTPA for PE. Methods We searched MEDLINE (1966 to March 2004) and EMBASE (1974 to 2004) using the terms pulmonary embolism, computed x-ray tomography, CTPA, angiography, sensitivity and specificity, prognosis, and recurrence. We augmented our search by reviewing the reference lists of retrieved articles and review articles, our personal files, and reference lists of related articles in our files. Our medical librarian performed an independent search to ensure completeness. The search was not limited to the English language, but only published reports were included (Figure 1). Figure 1. Flow diagram of study selection. Study Identification and Eligibility We attempted to identify all published studies that examined the rate of subsequent symptomatic venous thromboembolism (VTE) in patients who did not receive anticoagulation after negative or indeterminate CTPA results. To be included in the analysis, studies had to 1) have a consecutive sample or a well-defined reason for a selected sample (for example, inclusion of only patients with underlying cardiopulmonary disease or those referred to specialty centers); 2) define the diagnostic strategy used to confirm or exclude VTE; 3) withhold anticoagulation or clearly state the reason for administering anticoagulation when VTE was excluded (patients who received anticoagulation were excluded from the final analysis); 4) have a minimum of 3 months of follow-up; and 5) report subsequent symptomatic VTE events and the means of confirmation. Study Quality Two reviewers independently rated each studys quality. Because there are no validated tools for quality assessment of outcome studies, we adapted the McMaster criteria for evaluating the validity of studies about prognosis (23). Studies were assessed for presence of 9 features: description of patient sample characteristics, description of inclusion and exclusion criteria, potential selection bias, length of follow-up, completeness of follow-up, description of patients lost to follow-up, description of reasons for incomplete follow-up, definition of outcomes at the start of the study, and objectivity of outcomes. The intraclass correlation coefficient for agreement between the 2 raters on overall quality rating for all included studies was 0.85 (P< 0.001). Disagreements were resolved by consensus. In addition to abstracted data on patients, CTPA performance, and outcomes, we recorded the number of patients who had initial nondiagnostic CTPA results and follow-up of these patients if reported. Patients who received anticoagulation despite initial negative results on CTPA were excluded from the final analysis. Although some studies included a longer follow-up period, we limited our analysis to the first 3 months after negative results on CTPA because events after 3 months are likely to be new rather than recurrences. Statistical Analysis The rates of subsequent VTE events and fatal PE were calculated from the abstracted numbers for each study. Extracted outcomes were the proportion of individuals with negative results on CTPA who subsequently experienced pulmonary emboli, fatal or otherwise. These data were combined by using an approximation to the inverse variance approach, effectively weighting each study according to its sample size (24). The 95% CI for each study and for the overall effect was calculated by using exact binomial methods. Heterogeneity was assessed visually with Galbraith plots (25). Publication bias was assessed visually by using funnel plots and by statistically using the method of Egger and colleagues (26). The sensitivity of our results to potential publication bias was assessed by using the methods of Duval and Tweedie (27). We performed sensitivity analyses, assessing the effects of type of study (prospective vs. retrospective), year of study, whether patients were consecutive or selected, generation of computed tomography (CT) scanner, the thickness of CT cuts, caudocranial image acquisition, view box interpretation, and the prevalence of PE. Role of the Funding Source No funding was received in support of this review. Results We identified 640 abstracts in our search. Most were excluded because they did not include outcome data on patients not treated with anticoagulants (Figure 1). Among the 27 remaining articles, 4 were excluded: 3 had insufficient follow-up data (4, 28, 29) and 1 reported duplicate data (30) that were presented as part of the final report of a prospective study (31). Therefore, 23 articles were included in our analysis (3, 6, 11-13, 15, 17-19, 31-44). One of these (33) included 35 patients from another study (32). Qualitative Review The 23 studies included 15 prospective and 8 retrospective trials (Table). Study samples ranged from 54 to 1512, averaging 403 patients. Seventeen of the included studies examined consecutive patients, and 6 included selected patient samples. Overall, the mean prevalence of PE was 19.8% (range, 13% to 42%). Three studies (34, 37, 38) enrolled only patients in whom PE had been excluded and therefore did not report on prevalence in the sample. Nine of the studies included images obtained in the caudocranial direction, and 15 interpreted images on view box stations. The average CT scanner thickness was 2.1 mm (range, 2 to 5 mm). Ten prospective studies used CTPA with other diagnostic methods as part of a predetermined algorithm (3, 6, 11-13, 31-33, 35, 40). Pretest probability was used in 6 studies (6, 12, 13, 31, 32, 35), lung scintigraphy in 5 (11, 12, 31, 32, 35), lower-extremity compression ultrasonography in 6 (3, 13, 31-33, 40), and d-dimer testing in 4 (6, 11, 33, 40). Fourteen studies (3, 12, 13, 15, 17-19, 31, 33, 36, 37, 39, 41, 43) used objective imaging to confirm subsequent VTE events, while only 6 (3, 13, 15, 18, 34, 39) used autopsy confirmation or central adjudication to confirm fatal events. Table. Data Extracted from Individual Studies Twenty-one of the studies included a small proportion of patients (n= 492) who received anticoagulation despite negative results on CTPA. The reasons for anticoagulation included presence of deep venous thrombosis on concomitant ultrasonography (n= 70), chronic VTE (n= 68), and cardiac arrhythmias or other cardiac abnormalities (n= 204). Four patients had positive results on another test (ventilationperfusion scanning or CPA) that suggested PE, while 65 patients (13%) were listed as having nonthromboembolic disorders. The reason for anticoagulation was not stated in 63 patients. Only 18 patients received anticoagulation because of persistent high clinical suspicion of PE despite negative results on CTPA. These patients were not included in our analysis of outcomes. Overall quality ratings ranged from 3 to 9 (Appendix Table). Common quality problems included inadequately clear inclusion and exclusion criteria in 6 studies, potential selection bias in 16 studies, incomplete follow-up in 13 studies, inadequate description of the patients lost to follow-up in 14 studies, inadequate description of the reason for incomplete follow-up in 7 studies, and problems with the objectivity of outcome assessment in 9 studies. Appendix