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IMPORTANCE The use of perioperative, prophylactic, intravenous antibiotics is standard practice to reduce the risk of surgical site infection after oncologic resection and complex endoprosthetic reconstruction for lower extremity bone tumors. However, evidence guiding the duration of prophylactic treatment remains limited.OBJECTIVE To assess the effect of a 5-day regimen of postoperative, prophylactic, intravenous antibiotics compared with a 1-day regimen on the rate of surgical site infections within 1 year after surgery.DESIGN, SETTING, AND PARTICIPANTS This randomized clinical superiority trial was performed at 48 clinical sites in 12 countries from January 1, 2013, to October 29, 2019. The trial included patients with a primary bone tumor or a soft tissue sarcoma that had invaded the femur or tibia or oligometastatic bone disease of the femur or tibia with expected survival of at least 1 year who required surgical management by excision and endoprosthetic reconstruction. A total of 611 patients were enrolled, and 7 were exduded for ineligibility.INTERVENTIONS A 1- or 5-day regimen of postoperative prophylactic intravenous cephalosporin (cefazolin or cefuroxime) that began within 8 hours after skin closure and was administered every 8 hours thereafter. Those randomized to the 1-day regimen received identical saline doses every 8 hours for the remaining 4 days; patients, care providers, and outcomes assessors were blinded to treatment regimen.MAIN OUTCOMES AND MEASURES The primary outcome in this superiority trial was a surgical site infection (superficial incisional, deep incisional, or organ space) classified according to the criteria established by the Centers for Disease Control and Prevention within 1year after surgery. Secondary outcomes included antibiotic-related complications, unplanned additional operations, oncologic and functional outcomes, and mortality.RESULTS Of the 604 patients included in the final analysis (mean [SD] age, 41.2 [21.9] years; 361 [59.8%] male; 114 [18.9%] Asian, 43 [7.1%) Black, 34 [5.6%] Hispanic, 15 [2.5%] Indigenous, 384 [63.8%] White. and 12 [2.0%] other), 293 were randomized to a 5-day regimen and 311 to a 1-day regimen. A surgical site infection occurred in 44 patients (15.0%) allocated to the 5-day regimen and in 52 patients (16.7%) allocated to the 1-day regimen (hazard ratio, 0.93; 95% CI, 0.62-1.40; P = .73). Antibiotic-related complications occurred in 15 patients (5.1%) in the 5-day regimen and in 5 patients (1.6%) allocated to the 1-day regimen (hazard ratio, 3.24; 95% CI, 1.17-8.98; P = .02). Other secondary outcomes did not differ significantly between treatment groups.CONCLUSIONS AND RELEVANCE This randomized clinical trial did not confirm the superiority of a 5-day regimen of postoperative intravenous antibiotics over a 1-day regimen in preventing surgical site infections after surgery for lower extremity bone tumors that required an endoprosthesis. The 5-day regimen group had significantly more antibiotic-related complications.

Objectives: In the SPRINT trial, 18% of patients with a tibial shaft fracture (TSF) treated with intramedullary nailing (IMN) had one or more unplanned subsequent surgical procedures. It is clinically relevant for surgeon and patient to anticipate unplanned secondary procedures, other than operations that can be readily expected such as reconstructive procedures for soft tissue defects. Therefore, the objective of this study was to develop a machine learning (ML) prediction model using the SPRINT data that can give individual patients and their care team an estimate of their particular probability of an unplanned second surgery. Methods: Patients from the SPRINT trial with unilateral TSFs were randomly divided into a training set (80%) and test set (20%). Five ML algorithms were trained in recognizing patterns associated with subsequent surgery in the training set based on a subset of variables identified by random forest algorithms. Performance of each ML algorithm was evaluated and compared based on (1) area under the ROC curve, (2) calibration slope and intercept, and (3) the Brier score. Results: Total data set comprised 1198 patients, of whom 214 patients (18%) underwent subsequent surgery. Seven variables were used to train ML algorithms: (1) Gustilo-Anderson classification, (2) Tscherne classification, (3) fracture location, (4) fracture gap, (5) polytrauma, (6) injury mechanism, and (7) OTA/AO classification. The best-performing ML algorithm had an area under the ROC curve, calibration slope, calibration intercept, and the Brier score of 0.766, 0.954, -0.002, and 0.120 in the training set and 0.773, 0.922, 0, and 0.119 in the test set, respectively. Conclusions: An ML algorithm was developed to predict the probability of subsequent surgery after IMN for TSFs. This ML algorithm may assist surgeons to inform patients about the probability of subsequent surgery and might help to identify patients who need a different perioperative plan or a more intensive approach.

Background: Heterotopic ossification (HO) is a frequent complication following hip surgery. Using data from the Hip Fracture Evaluation with Alternatives of Total Hip Arthroplasty versus Hemiarthroplasty (HEALTH) trial, we aimed to (1) determine the prevalence of HO following total hip arthroplasty (THA) for femoral neck fracture in patients ≥50 years of age, (2) identify whether HO is associated with an increased risk of revision surgery within 24 months after the fracture, and (3) determine the impact of HO on functional outcomes. Methods: We performed a multivariable Cox regression analysis using revision surgery as the dependent variable and HO as the independent variable. We compared Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores between participants with and those without HO at 24 months. Results: Of 1,441 participants in the study, 287 (19.9%) developed HO within 24 months. HO was not associated with subsequent revision surgery. Grade-III HO was associated with statistically significant and clinically relevant deterioration in the total WOMAC score, which was mainly related to the function component of the score, compared with grade I or II. Conclusions: The impact of grade-III HO on the functional outcomes and quality of life after THA for hip fracture is clinically important, and HO prophylaxis for selected high-risk patients may be appropriate. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Question Does the probiotic Lactobacillus rhamnosus GG prevent ventilator-associated pneumonia (VAP) among critically ill patients? Findings In this randomized trial involving 2650 patients, no significant difference in VAP incidence was found among patients treated with probiotics compared with placebo (21.9% vs 21.3%, respectively; hazard ratio 1.03; 95% CI 0.87-1.22). Meaning These findings do not support the use of Lactobacillus rhamnosus GG for prevention of ventilator-associated pneumonia in critically ill patients requiring mechanical ventilation. Importance Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. Objective To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Design, Setting, and Participants Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Interventions Enteral L rhamnosus GG (1 x 10(10) colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. Main Outcomes and Measures The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Results Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Conclusions and Relevance Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. This clinical trial assessed whether Lactobacillus rhamnosus GG compared with placebo reduces ventilator-associated pneumonia and other clinically important outcomes for a broad range of critically ill patients.

Objectives HEALTH was a randomized controlled trial comparing total hip arthroplasty with hemiarthroplasty in low-energy displaced femoral neck fracture patients aged ≥50 years with unplanned revision surgery within 24 months of the initial procedure being the primary outcome. No significant short-term differences between treatment arms were observed. The primary objective of this secondary HEALTH trial analysis was to determine if any patient and surgical factors were associated with increased risk of revision surgery within 24 months after hip fracture. Methods We analyzed 9 potential factors chosen a priori that could be associated with revision surgery. The factors included age, body mass index, major comorbidities, independent ambulation, type of surgical approach, length of operation, use of femoral cement, femoral head size, and degree of femoral stem offset. Our statistical analysis was a multivariable Cox regression using reoperation within 24 months of index surgery as the dependent variable. Results Of the 1441 patients included in this analysis, 8.1% (117/1441) experienced reoperation within 24 months. None of the studied factors were found to be predictors of revision surgery (P > 0.05). Conclusion Both total and partial hip replacements are successful procedures in low-energy displaced femoral neck fracture patients. We were unable to identify any patient or surgeon-controlled factors that significantly increased the need for revision surgery in our elderly and predominately female patient population. One should not generalize our findings to an active physiologically younger femoral neck fracture population. Level of evidence Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Objectives To identify factors associated with the development of prolonged pain after hip fracture surgery. Design Secondary analysis of a randomized controlled trial. Setting Eighty hospitals in 10 countries. Patients/participants One thousand four hundred forty-one hip fracture patients in the HEALTH trial. Interventions Total hip arthroplasty or hemiarthroplasty. Main outcome measures Moderate-to-severe pain (at least 2 activities on the Western Ontario and McMaster Universities Osteoarthritis questionnaire pain subscale with scores ≥2) at 12 and 24 months after hip arthroplasty. Results Of 840 and 726 patients with complete baseline data and outcomes at 1-year and 2-year follow-up, 96 (11.4%) and 80 (11.0%) reported moderate-to-severe pain, respectively. An increased risk of pain at both 1 and 2 years after surgery was associated with reporting moderate-to-severe hip pain before fracture [absolute risk increase (ARI) 15.3%, 95% confidence interval (CI) 6.44%-24.35%; ARI 12.5%, 95% CI 2.85%-22.12%, respectively] and prefracture opioid use (ARI 15.6%, 95% CI 5.41%-25.89%; ARI 21.1%; 95% CI 8.23%-34.02%, respectively). Female sex was associated with an increased risk of persistent pain at 1 year (ARI 6.2%, 95% CI 3.53%-8.84%). A greater risk of persistent pain at 2 years was associated with younger age (≤79-year-old; ARI 6.3%; 95% CI 2.67%-9.91%) and higher prefacture functional status (ARI 10.7%; 95% CI 3.80%-17.64%). Conclusions Among hip fracture patients undergoing arthroplasty, approximately one in 10 will experience moderate-to-severe pain up to 2 years after surgery. Younger age, female sex, higher functioning prefracture, living with hip pain prefracture, and use of prescription opioids were predictive of persistent pain. Level of evidence Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND: Total hip arthroplasty (THA) has been argued to improve health-related quality of life (HRQoL) and function in femoral neck fracture patients compared with hemiarthroplasty (HA). The HEALTH trial showed no clinically important functional advantages of THA over HA. The current analysis explores factors associated with HRQoL and function in this population. METHODS: Using repeated measures regression, we estimated the association between HRQoL and function [Short Form-12 (SF-12) physical component score (PCS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score] and 23 variables. RESULTS: THA as compared to monopolar HA, but not bipolar HA, was more likely to improve PCS scores (adjusted mean difference [AMD] 1.88 points, P = 0.02), whereas higher American Society of Anesthesiologists score (AMD -2.64, P < 0.01), preoperative use of an aid (AMD -2.66, P < 0.01), and partial weight-bearing status postoperatively (AMD -1.38, P = 0.04) demonstrated less improvement of PCS scores over time. THA improved WOMAC function scores over time compared with monopolar HA (but not bipolar HA) (AMD -2.40, P < 0.01), whereas higher American Society of Anesthesiologists classification (AMD 1.99, P = 0.01) and preoperative use of an aid (AMD 5.39, P < 0.01) were associated with lower WOMAC function scores. Preoperative treatment for depression was associated with lower functional scores (AMD 7.73, P < 0.01). CONCLUSION: Patients receiving THA are likely to receive small and clinically unimportant improvements in health utility and function compared with those receiving monopolar HA and little improvement compared with those receiving bipolar HA. Patient-specific characteristics seem to play a larger role in predicting functional improvement among femoral neck fracture patients. LEVEL OF EVIDENCE: Prognostic Level II.

Contains fulltext : 228684.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To compare the 24-month risk of mortality between arthroplasty and internal fixation for undisplaced femoral neck fractures (FNFs). DESIGN: Retrospective cohort study. SETTING: Secondary data analysis of 2 multinational randomized controlled trials. PARTICIPANTS: Patients aged 50 years or older with a FNF. INTERVENTION: Arthroplasty (n = 1441), including total hip arthroplasty and hemiarthroplasty, performed for a displaced FNF versus internal fixation (n = 734), including sliding hip screw or multiple cancellous screws, performed for an undisplaced FNF. MAIN OUTCOME MEASUREMENT: The primary outcome was mortality within 24 months of injury. Secondary outcomes included reoperation and health-related quality of life. RESULTS: The 24-month mortality rate was 15.0% (n = 327). Arthroplasty was associated with a significant reduction in the odds of mortality [adjusted odds ratio (aOR): 0.56, 95% confidence interval (CI): 0.44-0.72, P < 0.01] compared with treatment with internal fixation. 11.4% (n = 248) of the study patients required reoperation within 24 months of injury. The odds of reoperation were 59% lower with arthroplasty treatment than with internal fixation (aOR: 0.41, 95% CI: 0.32-0.55, P < 0.01). The 24-month SF-12 physical component scores were 2.7 points higher in arthroplasty patients compared with internal fixation patients (95% CI: 1.6-3.8, P < 0.01). CONCLUSIONS: Our findings suggest arthroplasty for a FNF may reduce the risk of mortality and reoperation compared with internal fixation of undisplaced fractures. This finding is counter to many current surgical practices but consistent with a mounting body of evidence. Before widespread adoption of arthroplasty for undisplaced fractures, these results should be confirmed in a definitive comparative trial. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Contains fulltext : 228698.pdf (Publisher’s version ) (Closed access) BACKGROUND: Hip fractures are recognized as one of the most devastating injuries impacting older adults because of the complications that follow. Mortality rates postsurgery can range from 14% to 58% within one year of fracture. We aimed to identify factors associated with increased risk of mortality within 24 months of a femoral neck fracture in patients aged ≥50 years enrolled in the FAITH and HEALTH trials. METHODS: Two multivariable Cox proportional hazards regressions were used to investigate potential prognostic factors that may be associated with mortality within 90 days and 24 months of hip fracture. RESULTS: Ninety-one (4.1%) and 304 (13.5%) of 2247 participants died within 90 days and 24 months of suffering a femoral neck fracture, respectively. Older age (P < 0.001), lower body mass index (P = 0.002), American Society of Anesthesiologists (ASA) class III/IV/V (P = 0.004), use of an ambulatory aid before femoral neck fracture (P < 0.001), and kidney disease (P < 0.001) were associated with a higher risk of mortality within 24 months of femoral neck fracture. Older age (P = 0.03), lower body mass index (P = 0.02), use of an ambulatory aid before femoral neck fracture (P < 0.001), and having a comorbidity (P = 0.04) were associated with a higher risk of mortality within 90 days of femoral neck fracture. CONCLUSIONS: Our analysis found that factors that are indicative of a poorer health status were associated with a higher risk of mortality within 24 months of femoral neck fracture. We did not find a difference in treatment methods (internal fixation vs. joint arthroplasty) on the risk of mortality. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND: Among adults undergoing contemporary noncardiac surgery, little is known about the frequency and timing of death and the associations between perioperative complications and mortality. We aimed to establish the frequency and timing of death and its association with perioperative complications. METHODS: We conducted a prospective cohort study of patients aged 45 years and older who underwent inpatient noncardiac surgery at 28 centres in 14 countries. We monitored patients for complications until 30 days after surgery and determined the relation between these complications and 30-day mortality using a Cox proportional hazards model. RESULTS: We included 40 004 patients. Of those, 715 patients (1.8%) died within 30 days of surgery. Five deaths (0.7%) occurred in the operating room, 500 deaths (69.9%) occurred after surgery during the index admission to hospital and 210 deaths (29.4%) occurred after discharge from the hospital. Eight complications were independently associated with 30-day mortality. The 3 complications with the largest attributable fractions (AF; i.e., potential proportion of deaths attributable to these complications) were major bleeding (6238 patients, 15.6%; adjusted hazard ratio [HR] 2.6, 95% confidence interval [CI] 2.2–3.1; AF 17.0%); myocardial injury after noncardiac surgery [MINS] (5191 patients, 13.0%; adjusted HR 2.2, 95% CI 1.9–2.6; AF 15.9%); and sepsis (1783 patients, 4.5%; adjusted HR 5.6, 95% CI 4.6–6.8; AF 12.0%). INTERPRETATION: Among adults undergoing noncardiac surgery, 99.3% of deaths occurred after the procedure and 44.9% of deaths were associated with 3 complications: major bleeding, MINS and sepsis. Given these findings, focusing on the prevention, early identification and management of these 3 complications holds promise for reducing perioperative mortality. Study registration:ClinicalTrials.gov, no. NCT00512109.

The objective of this analysis is to evaluate the necessity of large clinical trials using FLOW trial data. The FLOW pilot study and definitive trial were factorial trials evaluating the effect of different irrigation solutions and pressures on re-operation. To explore treatment effects over time, we analyzed data from the pilot and definitive trial in increments of 250 patients until the final sample size of 2447 patients was reached. At each increment we calculated the relative risk (RR) and associated 95% confidence interval (CI) for the treatment effect, and compared the results that would have been reported at the smaller enrolments with those seen in the final, adequately powered study. The pilot study analysis of 89 patients and initial incremental enrolments in the FLOW definitive trial favored low pressure compared to high pressure (RR: 1.50, 95% CI: 0.75–3.04; RR: 1.39, 95% CI: 0.60–3.23, respectively), which is in contradiction to the final enrolment, which found no difference between high and low pressure (RR: 1.04, 95% CI: 0.81–1.33). In the soap versus saline comparison, the FLOW pilot study suggested that re-operation rate was similar in both the soap and saline groups (RR: 0.98, 95% CI: 0.50–1.92), whereas the FLOW definitive trial found that the re-operation rate was higher in the soap treatment arm (RR: 1.28, 95% CI: 1.04–1.57). Our findings suggest that studies with smaller sample sizes would have led to erroneous conclusions in the management of open fracture wounds. NCT01069315 (FLOW Pilot Study) Date of Registration: February 17, 2010, NCT00788398 (FLOW Definitive Trial) Date of Registration: November 10, 2008.

CONTEXT: Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping. OBJECTIVE: To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect. DATA SOURCES: Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008. STUDY SELECTION: Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs. DATA EXTRACTION: Reviewers with methodological expertise conducted data extraction independently. RESULTS: The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks

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. (C) 2014 Elsevier Inc. All rights reserved.

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. (C) 2013 Elsevier Inc. All rights reserved.

Background: There is uncertainty regarding the prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurements after noncardiac surgery. Methods: The current study undertook a systematic review and meta-analysis. The study used six search strategies and included noncardiac surgery studies that provided data from a multivariable analysis assessing whether a postoperative troponin or creatine kinase muscle and brain isoenzyme measurement was an independent predictor of mortality or a major cardiovascular event. Independent investigators determined study eligibility and abstracted data in duplicate. Results: Fourteen studies, enrolling 3,318 patients and 459 deaths, demonstrated that an increased troponin measurement after surgery was an independent predictor of mortality (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.2-5.2), but there was substantial heterogeneity (I(2) = 56%). The independent prognostic capabilities of an increased troponin value after surgery in the 10 studies that assessed intermediate-term (

Objective To investigate the impact of industry funding on reporting of subgroup analyses in randomised controlled trials. Design Systematic review. Data sources Medline. Study selection Randomised controlled trials published in 118 core clinical journals (defined by the National Library of Medicine) in 2007. 1140 study reports in a 1: 1 ratio by high (five general medicine journals with largest number of total citations in 2007) versus lower impact journals, were randomly sampled. Two reviewers, independently and in duplicate, used standardised, piloted forms to screen study reports for eligibility and to extract data. They also used explicit criteria to determine whether a randomised controlled trial reported subgroup analyses. Logistic regression was used to examine the association of prespecified study characteristics with reporting versus not reporting of subgroup analyses. Results 469 randomised controlled trials were included, of which 207 (44%) reported subgroup analyses. High impact journals (adjusted odds ratio 2.64, 95% confidence interval 1.62 to 4.33), non-surgical (versus surgical) trials (2.10, 1.26 to 3.50), and larger sample size (3.38, 1.64 to 6.99) were associated with more frequent reporting of subgroup analyses. The strength of association between trial funding and reporting of subgroups differed in trials with and without statistically significant primary outcomes (interaction P=0.02). In trials without statistically significant results for the primary outcome, industry funded trials were more likely to report subgroup analyses (2.29, 1.30 to 4.72) than non-industry funded trials. This was not true for trials with a statistically significant primary outcome (0.79, 0.46 to 1.36). Industry funded trials were associated with less frequent prespecification of subgroup hypotheses (31.3% v 38.0%, adjusted odds ratio 0.49, 0.26 to 0.94), and less use of the interaction test for analyses of subgroup effects (41.4% v 49.1%, 0.52, 0.28 to 0.97) than non-industry funded trials. Conclusion Industry funded randomised controlled trials, in the absence of statistically significant primary outcomes, are more likely to report subgroup analyses than non-industry funded trials. Industry funded trials less frequently prespecify subgroup hypotheses and less frequently test for interaction than non-industry funded trials. Subgroup analyses from industry funded trials with negative results for the primary outcome should be viewed with caution.

Context Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping. Objective To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect. Data Sources Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008. Study Selection Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs. Data Extraction Reviewers with methodological expertise conducted data extraction independently. Results The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks

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 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.