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Background: Myocardial injury after noncardiac surgery (MINS) is common and associated with short- and long-term major cardiovascular events. Diagnostic criteria for MINS using Abbott high-sensitivity cardiac troponin I (hs-cTnI) are unknown., Methods: We performed a prospective cohort study of adults who had in-patient noncardiac surgery and measured hs-cTnI (Abbott Laboratories) on postoperative serum samples collected up to postoperative day 3. The objective was to determine prognostically important hs-cTnI thresholds associated with major cardiac events and death at 30 days after noncardiac surgery. Using Cox proportional iterative analyses, we determined peak postoperative hs-cTnI thresholds associated with the occurrence of the 30-day composite of major cardiac events (ie, nonfatal myocardial infarction after 3 postoperative days, cardiac arrest, and congestive heart failure) and death., Results: Of 3953 included patients, 66 (1.7%) experienced the primary outcome at 30 days. Peak hs-cTnI values and associated incidence of major cardiac events and death were as follows: < 60 ng/L: 1.0% (95% CI 0.7-1.3); 60 to < 700 ng/L: 8.6% (5.6-13.0); and ≥ 700 ng/L: 27.3% (16.4-41.9). Compared with peak hs-cTnI < 60 ng/L, adjusted hazard ratios were 7.54 (95% CI% 4.27-13.32) for hs-cTnI values of 60 to < 700 ng/L and 26.87 (13.27-54.41) for values ≥ 700 ng/L., Conclusions: Hs-cTnI elevation within the first 3 days after noncardiac surgery independently predicts major cardiac events and death at 30 days. A postoperative hs-cTnI ≥ 60 ng/L was associated with a > 7-fold increase in the risk of subsequent major cardiac events and mortality at 30 days., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Tobacco smoking is a leading preventable cause of death and increases perioperative risk. Determinants of smoking abstinence after noncardiac surgery and the association between smoking and 1-yr vascular outcomes are not fully elucidated., Methods: We did a prospective cohort study of 40 004 patients, aged ≥45 yr, enrolled between August 2007 and November 2013, and followed for 1 yr after surgery. Patients were categorised as never smokers, ex-smokers (quit >4 weeks preoperatively), and current smokers (smoking ≤4 weeks preoperatively). Primary outcome was abstinence at 1 yr. Secondary outcome was a composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke at 1 yr., Results: Of 4658 current smokers, 1838 (39.5%) were abstinent 1 yr after surgery. Median (inter-quartile range) time to resumption was 7 (3-23) days post-surgery. Perioperatively, 7.2% of current smokers obtained smoking cessation pharmacotherapy. Older age (adjusted risk ratio [aRR] 1.21; 95% confidence interval [CI]: 1.12-1.32); having recent coronary artery disease (aRR 1.41; 95% CI: 1.29-1.55); cancer (aRR 1.37; 95% CI: 1.18-1.59); and undergoing major vascular (aRR 1.20; 95% CI: 1.02-1.41), urgent/emergent (aRR 1.14; 95% CI: 1.05-1.23), or thoracic (aRR 1.41; 95% CI: 1.26-1.56) surgeries increased abstinence. One-year abstinence was less likely when patients stopped smoking 0-1 day (aRR 0.53; 95% CI: 0.43-0.66) and 2-14 days (aRR 0.76; 95% CI: 0.71-0.82) before surgery compared with >14 days before surgery. Current smokers (adjusted hazard ratio [aHR] 1.14; 95% CI: 1.01-1.29) and ex-smokers (aHR 1.11; 95% CI: 1.03-1.21) had higher risk of the 1-yr vascular outcome compared with never smokers., Conclusions: Long-term tobacco abstinence is more likely after major surgery in those with serious medical comorbidities. Interventions to prevent smoking resumption after surgery remain a priority. Clinical trial registration NCT00512109., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Prognostic factors in lung transplantation are those variables that are associated with transplant outcomes. Knowledge of donor and recipient prognostic variables can aid in the optimal allocation of donor lungs to transplant recipients and can also inform post-operative discussions with patients about prognosis. Current research findings related to prognostic factors in lung transplantation are inconsistent and the relative importance of various factors is unclear. This review aims to provide the best possible estimates of the association between putative prognostic variables and 1-year all-cause mortality in adult lung transplant recipients., Methods: We searched 5 bibliographic databases for studies assessing the associations between putative predictors (related to lung donors, recipients, or the transplant procedure) and 1-year recipient mortality. We pooled data across studies when justified and utilized GRADE methodology to assess the certainty in the evidence., Results: From 72 eligible studies (2002-2020), there were 34 recipient variables, 4 donor variables, 10 procedural variables, and 7 post-transplant complication variables that were amenable to a meta-analysis. With a high degree of certainty in the evidence only post-transplant need for extra-corporeal membrane oxygenation (ECMO) (HR 1.91, 95% CI 1.79-2.04) predicted 1-year mortality. No donor variables appeared to predict transplant outcome with high or even moderate certainty., Conclusion: Across the range of contemporary donors and recipients that clinicians accept for lung transplantation, this review, with high certainty, found 1 prognostic factor that predicted 1-year mortality, and 37 additional factors with a moderate degree of certainty. The lack of prognostic significance for some widely accepted factors (e.g., donor smoking, age) likely relates to existing limits in the range of these variables at the time of donor and recipient selection., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose: Femoral neck fractures in young patients are typically managed with internal fixation using either cancellous screws or a sliding hip screw (SHS). Although fixation preserves the hip joint, patients are still at risk of complications and poor clinical outcomes which lead to diminished function and health related quality of life (HRQL). The Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2) pilot randomized controlled factorial trial evaluated the effect of surgical fixation (cancellous screws vs. SHS) and vitamin D supplementation vs. placebo on patient-reported function and HRQL., Methods: Patients between the ages of 18-60 years with a femoral neck fracture requiring surgical fixation were eligible. Eligible patients were randomized to receive either a sliding hip screw or cancellous screws for fracture fixation AND vitamin D 3 4,000 IU or placebo daily for 6 months. Patient-reported function (Hip Outcome Score) and HRQL (Short Form-12) were assessed at standardized time points in the 12 months following their fixation surgery. Patient-reported function and HRQL were summarized using means, SD, and 95% confidence intervals (CIs), or percentages and counts. Longitudinal data analysis with mixed models was used to explore the effect of treatment group and time on the patient-reported function and HRQL., Results: 86 of the 91 patients randomized into the FAITH-2 pilot study were deemed eligible. There were no significant differences in patient-reported function or HRQL between the treatment groups at 12 months post-fracture. At the 6- and 9-month assessments, a potential benefit in hip function was seen in the cancellous screw group. In all treatment groups, participants reported lower function and HRQL at 12 months post-fracture as compared to their pre-injury assessment., Conclusions: Few differences were found in function and HRQL among the treatment groups in the FAITH-2 pilot study. Despite modern implants and vitamin D supplementation, neither function nor HRQL returns to baseline in this population. Additional efforts to improve the outcomes of these challenging injuries are still needed., Level of Evidence: Therapeutic Level II., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To provide GRADE guidance for assessing risk of bias across an entire body of evidence consequent on missing data for systematic reviews of both binary and continuous outcomes., Study Design and Setting: Systematic survey of published methodological research, iterative discussions, testing in systematic reviews, and feedback from the GRADE Working Group., Results: Approaches begin with a primary meta-analysis using a complete case analysis followed by sensitivity meta-analyses imputing, in each study, data for those with missing data, and then pooling across studies. For binary outcomes, we suggest use of "plausible worst case" in which review authors assume that those with missing data in treatment arms have proportionally higher event rates than those followed successfully. For continuous outcomes, imputed mean values come from other studies within the systematic review and the standard deviation (SD) from the median SDs of the control arms of all studies., Conclusions: If the results of the primary meta-analysis are robust to the most extreme assumptions viewed as plausible, one does not rate down certainty in the evidence for risk of bias due to missing participant outcome data. If the results prove not robust to plausible assumptions, one would rate down certainty in the evidence for risk of bias., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Platelet transfusions are commonly used to treat critically ill patients with thrombocytopenia. Whether platelet transfusions are associated with a reduction in the risk of major bleeding is unknown., Patients/methods: Observational cohort study nested in a previous multicenter, randomized thromboprophylaxis trial in the intensive care unit (ICU). The objective was to evaluate the association between platelet transfusions and adjudicated major bleeding events. Platelet transfusion episodes were reviewed for timing of administration, product type, and dose. Major bleeding with and without platelet transfusions was adjusted for severity of thrombocytopenia, use of anti-platelet agents, surgery and other covariates. Secondary outcomes were thrombosis, death in ICU and platelet count increment., Results: Among 2,256 patients, 71 (3.1%) received 190 platelet transfusions. Of those, 121 (63.7%) were administered to 54 non-bleeding, thrombocytopenic patients. Adjusted rates of major bleeding were not statistically different with or without the administration of platelet transfusions (hazard ratio for transfused patients 0.85; 95% confidence interval, 0.42-1.72). We did not find a significant association between platelet transfusion use and thrombosis or death in ICU in adjusted analyses. Thrombocytopenia, anemia, major or minor bleeding and use of anticoagulants were associated with platelet transfusion administration. The median post-transfusion platelet count increment was 20×10 9 /L at 3.5 hours post-transfusion., Conclusions: Rates of major bleeding were not different for patients who did and did not receive platelet transfusions. Inferences were limited by the small number of transfused patients. Clinical trials are needed to better investigate the potential hemostatic benefit and potential harms of platelet transfusions for this high-risk population.

Objectives: We explored how readers interpret authors' roles based on authorship order and corresponding author., Study Design and Setting: We conducted a cross-sectional survey of all 291 Surgical and Medical Chairpersons across North America. We developed hypothetical study and authorship bylines with five authors varying the corresponding author as first or last author. Respondents reported their perceptions about the authors' roles in the study and the most prestigious authorship position. We used multinomial regression to explore the results., Results: One hundred sixty-five chairpersons (response rate: 57%) completed our survey. When the first author was designated as corresponding author, most of the respondents assumed that this author had taken the lead in study design (55.3%) and analysis and interpretation of data (51.2%). When the last author (fifth) was designated as corresponding, perceptions of the first author's role in study concept and design (odds ratio [OR] = 0.25, 95% confidence interval [CI]: 0.15, 0.41) and analysis and interpretation of results (OR = 0.22, 95% CI: 0.13, 0.38) decreased significantly. Overall prestige of the last author position increased significantly when designated as corresponding author (OR = 4.0, 95% CI: 2.4, 6.4)., Conclusions: Academic department chairs' perception of authors' contributions was influenced by corresponding author designation. Without authors' explicit contributions in research articles, many readers may draw false conclusions about author credit and accountability., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: We previously developed an approach to address the impact of missing participant data in meta-analyses of continuous variables in trials that used the same measurement instrument. We extend this approach to meta-analyses including trials that use different instruments to measure the same construct., Methods: We reviewed the available literature, conducted an iterative consultative process, and developed an approach involving a complete-case analysis complemented by sensitivity analyses that apply a series of increasingly stringent assumptions about results in patients with missing continuous outcome data., Results: Our approach involves choosing the reference measurement instrument; converting scores from different instruments to the units of the reference instrument; developing four successively more stringent imputation strategies for addressing missing participant data; calculating a pooled mean difference for the complete-case analysis and imputation strategies; calculating the proportion of patients who experienced an important treatment effect; and judging the impact of the imputation strategies on the confidence in the estimate of effect. We applied our approach to an example systematic review of respiratory rehabilitation for chronic obstructive pulmonary disease., Conclusions: Our extended approach provides quantitative guidance for addressing missing participant data in systematic reviews of trials using different instruments to measure the same construct., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Thrombocytopenia is the most common hemostatic disorder in critically ill patients. The objective of this study was to describe the incidence, risk factors, and outcomes of thrombocytopenia in patients admitted to medical-surgical ICUs., Methods: Three thousand seven hundred forty-six patients in 67 centers were enrolled in a randomized trial in which unfractionated heparin was compared with low-molecular-weight heparin (LMWH) for thromboprophylaxis. Patients who had baseline platelet counts < 75 × 10(9)/L or severe coagulopathy at screening were excluded. We analyzed the risk of developing mild (100-149 × 10(9)/L), moderate (50-99 × 10(9)/L), and severe (< 50 × 109/L) thrombocytopenia during an ICU stay. We also assessed independent and time-varying predictors of thrombocytopenia and the effect of thrombocytopenia on major bleeding, transfusions, and death., Results: The incidences of mild, moderate, and severe thrombocytopenia were 15.3%, 5.1%, and 1.6%, respectively. The predictors of each category of thrombocytopenia were APACHE (Acute Physiology and Chronic Health Evaluation) II score, use of inotropes or vasopressors, and renal replacement therapy. The risk of moderate thrombocytopenia was lower in patients who received LMWH thromboprophylaxis but higher in surgical patients and in patients who had liver disease. Each category of thrombocytopenia was associated with subsequent bleeding and transfusions. Moderate and severe thrombocytopenia were associated with increased ICU and hospital mortality., Conclusion: A high severity of illness, prior surgery, use of inotropes or vasopressors, renal replacement therapy, and liver dysfunction are associated with a higher risk of thrombocytopenia developing in the ICU, whereas LMWH thromboprophylaxis is associated with a lower risk. Patients who develop thrombocytopenia in the ICU are more likely to bleed, receive transfusions, and die.

Background: In a recent multicenter randomized trial comparing unfractionated heparin (UFH) with low-molecular-weight heparin (dalteparin) for thromboprophylaxis in 3,746 critically ill patients, 17 patients (0.5%) developed heparin-induced thrombocytopenia (HIT) based on serotonin-release assay-positive (SRA+) status. A trend to a lower frequency of HIT with dalteparin vs UFH was observed in the intention-to-treat analysis (five vs 12 patients, P = .14), which was statistically significant (three vs 12 patients, P = .046) in a prespecified per-protocol analysis that excluded patients with DVT at study entry. We sought to characterize HIT outcomes and to determine how dalteparin thromboprophylaxis may reduce HIT frequency in patients in the ICU., Methods: In 17 patients with HIT, we analyzed platelet counts and thrombotic events in relation to the study drug and other open-label heparin, to determine whether the study drug plausibly explained seroconversion to SRA+ status and/or breakthrough of thrombocytopenia/thrombosis. We also compared antibody frequencies (dalteparin vs UFH) in 409 patients serologically investigated for HIT., Results: HIT-associated thrombosis occurred in 10 of 17 patients (58.8%) (8:1:1 venous:arterial:both). Dalteparin was associated with fewer study drug-attributable HIT-related events (P = .020), including less seroconversion (P = .058) and less breakthrough of thrombocytopenia/thrombosis (P = .032). Antiplatelet factor 4/heparin IgG antibodies by enzyme-linked immunosorbent assay were less frequent among patients receiving dalteparin vs UFH (13.5% vs 27.3%, P &lt; .001). One patient with HIT-associated DVT died after UFH bolus (anaphylactoid reaction), whereas platelet counts recovered in two others with HIT-associated VTE despite continuation of therapeutic-dose UFH., Conclusions: The lower risk of HIT in patients in the ICU receiving dalteparin appears related to both decreased antibody formation and decreased clinical breakthrough of HIT among patients forming antibodies.

Background: No methods directly address the impact of missing participant data for continuous outcomes in systematic reviews on risk of bias., Methods: We conducted a consultative, iterative process to develop a framework for handling missing participant data for continuous outcomes. We considered sources reflecting real observed outcomes in participants followed-up in individual trials included in the systematic review, and developed a range of plausible strategies. We applied our approach to two systematic reviews., Results: We used five sources of data for imputing the means for participants with missing data. To impute standard deviation (SD), we used the median SD from the control arms of all included trials. Using these sources, we developed four progressively more stringent imputation strategies. In the first example review, effect estimates diminished and lost significance as strategies became more stringent, suggesting rating down confidence in estimates of effect for risk of bias. In the second, effect estimates maintained statistical significance using even the most stringent strategy, suggesting missing data does not undermine confidence in results., Conclusions: Our approach provides a useful, reasonable, and relatively simple, quantitative guidance for judging the impact of risk of bias as a result of missing participant data in systematic reviews of continuous outcomes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Surrogate markers are often used in clinical trials if too much time or expense is involved to observe the effect of treatment on patient-important outcomes. We wished to estimate the ultimate effects of treatment when randomized trials have addressed only a surrogate marker, and additional, independent studies evaluate the association between the surrogate and the final outcome., Study Design and Setting: We show how to calculate the overall effect of treatment on a final outcome, together with its standard error and confidence interval. The methods are illustrated with data on the effect of therapy on hepatitis B seroconversion, a surrogate marker, and its association with patient-important outcomes (cirrhosis and liver cancer)., Results: We find that the effect of treatment on the final outcome may be small even if there are strong associations between treatment and the surrogate and between the surrogate and the patient-important outcome., Conclusion: Apparently, robust treatment effects on surrogates are likely to lead to small and uncertain effects on patient-important outcomes. We should be cautious in advising patients to adopt a therapy when compelling evidence is restricted to its impact on surrogate outcomes, particularly if that therapy may be toxic or otherwise cause harms., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To test the reliability and validity of specific instructions to classify blinding, when unclearly reported in randomized trials, as "probably done" or "probably not done.", Study Design and Setting: We assessed blinding of patients, health care providers, data collectors, outcome adjudicators, and data analysts in 233 randomized trials in duplicate and independently using detailed instructions. The response options were "definitely yes," "probably yes," "probably no," and "definitely no." We contacted authors for data verification (46% response). For each of the five questions, we assessed reliability by calculating the agreement between the two reviewers and validity by calculating the agreement between reviewers' consensus and verified data., Results: The percentage with unclear blinding status varied between 48.5% (patients) and 84.1% (data analysts). Reliability was moderate for blinding of outcome adjudicators (κ=0.52) and data analysts (κ=0.42) and substantial for blinding of patients (κ=0.71), providers (κ=0.68), and data collectors (κ=0.65). The raw agreement between the consensus record and the author-verified record varied from 84.1% (blinding of data analysts) to 100% (blinding of health care providers)., Conclusion: With the possible exception of blinding of data analysts, use of "probably yes" and "probably no" instead of "unclear" may enhance the assessment of blinding in trials., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Recently, results from the large, randomized study to prospectively evaluate reamed intramedullary nails in patients with tibial fractures (SPRINT) trial suggested a benefit for reamed intramedullary nail insertion in patients with closed tibial shaft fractures largely based on cost-neutral autodynamizations and a potential advantage for unreamed intramedullary nailing in open fractures. We performed an economic evaluation to compare resource use and effectiveness of reamed and unreamed intramedullary nailing using a cost-utility analysis., Methods: We calculated quality-adjusted life years (QALYs) for each patient from a self-administered health utility index 3 questionnaire for the first 12 months following the intramedullary nailing. A convenience sample of 235 SPRINT patients provided data on costs associated with health care resource utilization. All costs are reported in Canadian dollars for the 2008 financial year., Results: We found incremental effects of -0.017 (95% confidence interval [CI] -0.021-0.058) and -0.002 (95% CI -0.060-0.062) QALYs for patients treated with reamed compared with unreamed intramedullary nails in closed and open fractures, respectively. The incremental costs for reamed compared with unreamed intramedullary nailing were $51 Canadian dollars (95% CI -$2298-$2400) in closed tibial fractures and $2546 Canadian dollars (95%CI -$1773-$6864) in open tibial fractures. Unreamed nailing dominated reamed nailing for both closed and open tibial fractures; however, the cost and the utility results had high variability., Conclusion: Our economic analysis from a governmental perspective suggests small differences in both cost and effectiveness with large uncertainty between reamed and unreamed intramedullary nailing., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objective: To examine the effect of brief disease-specific education delivered in primary care on objective measures of knowledge in individuals recently diagnosed with chronic obstructive pulmonary disease (COPD)., Methods: A randomized control trial was undertaken during which an experimental group received 2h of education delivered by a certified COPD educator and a control group received usual care. The Bristol COPD Knowledge Questionnaire (BCKQ) was self-administered at the time of randomization and approximately three months later., Results: Of the 93 individuals that completed the study, 50 (forced expiratory volume in 1s [FEV(1)]=60.0+/-14.3% predicted; 22 males) and 43 (FEV(1)=58.2+/-14.4% predicted; 20 males) participants were randomized to the experimental and control groups, respectively. The BCKQ increased from 27.6+/-8.7 to 36.5+/-7.7 points (p<0.001) in the experimental group, which was greater than any seen in the control group (between-group difference 8.3, 95% confidence interval 5.5-11.2 points)., Conclusion: As little as 2h of education delivered in primary care was effective at increasing objective measures of disease-specific knowledge., Practice Implications: A program of brief education delivered in the primary care setting, represents an important approach for many individuals with COPD who are unlikely to access pulmonary rehabilitation., ((c) 2009. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To compare the Short Musculoskeletal Function Assessment Dysfunction Index (SMFA DI) and the Short Form-36 Physical Component Summary (SF-36 PCS) scores among patients undergoing operative management of tibial fractures., Study Design and Setting: Between July 2000 and September 2005, we enrolled 1,319 skeletally mature patients with open or closed fractures of the tibial shaft that were managed with intramedullary nailing. Patients were asked to complete the SMFA Questionnaire and SF-36 at discharge and 3, 6, and 12 months post-surgical fixation., Results: The SMFA DI and SF-36 PCS scores were highly correlated at 3, 6, and 12 months post-surgical fixation. The difference in the mean standardized change scores for SMFA DI and SF-36 PCS, from 3 to 12 months post-surgical fixation, was not statistically significant. Both the SMFA DI and SF-36 PCS scores were able to discriminate between healed and nonhealed tibial fractures at 3, 6, and 12 months postsurgery., Conclusion: In patients with tibial-shaft fractures, the SMFA DI offered no significant advantages over the SF-36 PCS score. These results, along with the usefulness of SF-36 for comparing populations, recommend the SF-36 for assessing physical function in studies of patients with tibial fractures.

Objective: To devise and test techniques to blind outcome assessors in trials of hip fracture fixation., Study Design and Setting: We developed three techniques (Blackout, Subtraction, and Overlay) to mask radiographs of hip fractures fixated with cancellous screws or dynamic hip screws. Fifty orthopedic trauma surgeons each assessed 32 radiographs blinded with each technique., Results: All techniques achieved low rates of correct identification of screw type (14.9% for Blackout, 26.9% for Subtraction, 22.1% for Overlay) and high proportions of "don't know" responses (72.3%, 48.4%, 52.8%, respectively). The interrater reliability of reduction quality in the blinded images (intraclass correlation coefficient [ICC]=0.55-0.57) was similar to the reliability of the unblinded radiographs (ICC=0.60). Surgeons perceived 6.9% of the Overlay images as much more difficult to rate than unblinded radiographs, compared with 9.7% of Subtraction images (P=0.25) and 28.0% of Blackout images (P<0.001)., Conclusion: Three techniques of blinding radiographs of femoral neck fractures successfully mask surgeons to the type of implant fixated, do not compromise reliability of reduction ratings, and do not make rating most radiographs more difficult. Trialists should explore creative approaches to optimize blinding when designing trials, and should incorporate rigorous approaches to testing blinding success.

Objective: To determine relative responsiveness of disease-specific and generic preference-based health-related quality of life instruments in gastroesophageal reflux disease (GERD)., Study Design and Setting: We compared standardized response means (SRM) of disease-specific and preference-based instruments in 217 outpatients with GERD., Results: Quality of Life in Reflux and Dyspepsia and symptom scores were responsive across all domains, whereas global rating of change and Work Productivity and Activity Impairment-GERD only in single domains. The most responsive were Quality of Life in Reflux and Dyspepsia food/drink problems (SRM: 1.90, 95% confidence interval [CI]: 1.76-2.03) and vitality (SRM: 1.68, 95% CI 1.55-1.82) domains, Work Productivity and Activity Impairment-GERD workdays with reflux symptoms (SRM: 2.02, 95% CI 1.84-2.19), symptoms of heartburn (SRM: 1.83, 95% CI 1.69-1.96) and acid reflux (SRM: 1.48, 95% CI 1.35-1.62), and global rating of change in stomach problems (SRM: 2.19, 95% CI 2.05-2.32). The least responsive were Work Productivity and Activity Impairment-GERD domains related to hours absent at work (SRM: 0.22, 95% CI 0.05-0.38), reduced productivity at work (SRM: 0.66, 95% CI 0.48-0.83) and during other activities (SRM: 0.78, 95% CI 0.65-0.92), as well as emotional global rating of change (SRM: 0.72, 95% CI 0.58-0.85), and the standard gamble (SRM: 0.35, 95% CI 0.21-0.48), which was less responsive than the feeling thermometer (SRM: 0.92, 95% CI 0.78-1.05)., Conclusions: In patients with GERD, disease-specific health-related quality of life instruments and symptom scores showed greater responsiveness than preference-based generic instruments. The feeling thermometer proved more responsive than the standard gamble.

Objectives: Recent studies suggest that rating clinical marker states (CMS) does not improve the measurement properties of the standard gamble (SG) and only slightly improves those of the feeling thermometer (FT). The poor intrarater (test-retest) reliability of CMS may explain their meager performance. Further, lack of interrater reliability may compromise the use of CMS in interpreting health state ratings. The aim of this study was to assess the reliability of CMS ratings for the SG and the FT., Study Design and Setting: Two similar studies in patients with chronic obstructive pulmonary disease (COPD, n=91) and in patients with gastroesophageal reflux disease (GERD, n=112) provided data for this analysis. Patients rated three different CMS (mild, moderate, and severe disease) twice several weeks apart. We used generalizability theory to calculate reliability coefficients., Results: Test-retest reliability for CMS ratings was higher for the FT compared to the SG (COPD: 0.86 vs. 0.67; GERD: 0.86 vs. 0.67). Interrater reliability was much higher for the FT compared to the SG (COPD: 0.78 vs. 0.46; GERD: 0.71 vs. 0.26)., Conclusions: These results suggest that the markedly poorer reliability of CMS for the SG than the FT is driven largely by poor interrater reliability.

Objective: To examine how authors of systematic reviews that include randomized clinical trials (RCTs) that are stopped early for benefit (truncated RCTs-tRCTs) address the potential for overestimation of treatment effects and to determine the weight of the tRCTs on pooled results., Study Design and Setting: We searched the Cochrane Library and MEDLINE and evaluated systematic reviews that include at least one tRCT. We documented approaches that authors used to address potential overestimates of treatment effect introduced by including tRCTs. We assessed the impact of tRCTs in meta-analyses on the outcomes that led to their early termination., Results: Of 96 systematic reviews that included at least one tRCT, 44 (46%) included >1 tRCT, 68 (71%) did not mention truncation at all, and 2 (2%) documented early stopping for benefit as a criterion for methodological quality. Of 47 meta-analyses in which authors reported, or we could calculate the contribution of the tRCTs to the pooled result, the tRCTs contributed more than 40% of the weight in 16/47 (34%)., Conclusion: Most systematic reviews and meta-analyses including tRCTs fail to consider the possible overestimates of effect that may result from early stopping for benefit. We recommend safeguards that address this possibility.

Objective: Effectively evaluating disease-modifying effects in clinical trials has posed a problem for clinical trialists and drug development. One method that has been proposed to evaluate disease-modifying effects has been the re-randomization of active group participants to discontinue the intervention after a period sufficient to produce therapeutic effects. We aimed to determine if this design would permit inferences regarding disease modification in a trial evaluating Pegaptanib sodium, an intra-ocular injection, for the treatment of age-related macular degeneration., Study Design and Setting: In two identically designed trials, 1,186 patients were randomized to receive 54 weeks of treatment. After 54 weeks, 1,053 were re-randomized to either stay on treatment or discontinue treatment. Patients were seen at multicenter outpatient clinics., Results: We found that patients randomized to discontinue treatment after 54 weeks of treatment and followed for a further 48 weeks, were significantly different than the control group (sham) in loss of 15 letters of vision (Relative Risk 0.70, 95% Confidence Interval 0.57-0.88, P=0.002), indicating that treatment is disease modifying. This effect was consistent throughout our sensitivity analyses., Conclusion: This trial is the first example of a clinical trial evaluating disease-modifying effects and this design should influence drug discovery to determine further therapeutic potential of pharmacologic interventions.

Background: A number of studies compared the quality, efficacy and tolerability of oral sodium phosphate (NaP) and polyethylene glycol (PEG)-based solutions in preparation for colonoscopy. The primary aim of this study was to explore whether endoscopists can be effectively blinded to the type of bowel preparation., Methods: We recruited 3 experienced endoscopists and 57 outpatients (18-65 years old) undergoing colonoscopy. We randomized eligible patients to receive one of the two bowel preparations. Endoscopists who performed the tests were blinded to the type of preparation, and made their best judgment on the type and quality of the bowel preparation., Results: Forty-five patients completed the study. The overall correct estimation of the type of bowel preparation was 60.0% (95% CI; 45.5%, 73.0%). The cleansing quality did not differ between the two preparations. Patients found oral NaP solution much easier to take (81.8% versus 36.4%; P = 0.005) and the PEG-based group tended to have more nausea or vomiting. 47.6% of patients in the PEG group indicated they would prefer to try another bowel preparation in the future compared to 4.5% in the oral NaP group (P = 0.002). We stopped the study after an interim analysis indicating that more than 600 patients would be required to detect statistically significant differences in the primary aim., Conclusion: Our findings suggest that blinding of endoscopists in clinical trials comparing oral NaP to PEG had a relatively low likelihood of bias. The study also suggests that oral NaP is easier to take and more tolerable than PEG without impairing cleansing quality.

Objective: This systematic review summarizes the evidence from randomized clinical trials of bright light therapy for treatment of premenstrual dysphoric disorder., Study Design: The authors performed a systematic review and meta-analysis of randomized clinical trials. They searched MEDLINE, AMED, CINAHL, Digital Dissertations, EMBASE, and the Cochrane Central Register of Controlled Trials. The main outcome measure was the change in depressive symptom scores as measured by the Hamilton Depression Rating Scale and the Beck Depression Inventory., Results: Four crossover trials studying a total of 55 participants met inclusion criteria. Three trials showed similar results; one fully unblinded trial showed a much larger effect. The pooled effect size from the random-effects model of the 3 higher quality trials was -0.20 (95% CI -0.48 to 0.07)., Conclusion: The small size of trials and correspondingly wide confidence limits, and methodologic limitations of the trials, leaves the impact of bright light therapy for relief of premenstrual depressive symptoms uncertain. The current evidence justifies neither enthusiastic dissemination nor confident rejection of this therapeutic modality.

Background: We aimed to determine if specialist journals implement specific Consolidated Standards for Reporting Trials (CONSORT) recommendations to the same extent as general medical journals., Methods: Analysis of random controlled trials (RCTs) in five general medical journals (n=100) and 10 specialist journals (n=100), all endorsing CONSORT. We evaluated the likelihood of reporting important methodologic criteria. Analyses controlled for the nested effect of journal within each journal type., Results: General medical journals published, on average, more CONSORT items per RCT than specialist journals (7.9 [SD 1.8] vs. 6.5 [SD 2.2] out of 11 possible items, P=.02). When compared with specialist journals, RCTs in general medical journals published a participant flow diagram more frequently (83 vs. 42%, odds ratio [OR] 6.7, 95% confidence interval [CI] 3.4-12.9) and more likely to report the method of randomization (78 vs. 55%, OR 2.9, 95% CI 1.5-5.3) and allocation concealment (48 vs. 26%, OR 2.6, 95% CI 1.4-4.7); they were less likely to publish RCTs reporting adverse events (58 vs. 78%, OR 0.3, 95% CI 0.2-0.7). Both page length and impact factor were weakly associated with number of CONSORT items reported., Conclusion: General medical and specialist journals that endorse CONSORT do not enforce reporting issues consistently, with specialty journals lagging behind general medical journals.

Background and Objective: Readers of randomized controlled trials (RCTs) commonly assume that what was not reported did not occur. We undertook an observational study to determine whether concealment of randomization or blinding was used in RCTs that failed to report these bias-reducing strategies., Methods: We recorded the reporting of concealment of randomization and blinding in 105 RCTs. We subsequently contacted the authors and determined if they had used these methodological safeguards., Results: We successfully obtained data from 98 authors. The authors in the full-text publications of these 98 RCTs failed to report the presence or absence of concealment of randomization in 55%, and the blinding status of participants in 26%, health care providers in 64%, data collectors in 84%, outcome assessors in 83%, and data analysts in 96%. In direct contact, authors frequently reported concealing randomization (96%; 95% confidence interval CI=87-100%), blinding participants (20%; 95% CI=7-41%), blinding health care providers (65%; 95% CI=52-77%), blinding data collectors (65%; 95% CI=53-75%), blinding outcome assessors (79%; 95% CI=69-87%), and blinding data analysts (50%; 95% CI=40-60%), despite not reporting the use of these methodological safeguards in their publications., Conclusions: Readers should not assume that bias-reducing procedures not reported in an RCT did not occur.