Compliance-Adjusted Estimates of Aspirin Effects Among Older Persons in the ASPREE Randomized Trial.

The Aspirin in Reducing Events in the Elderly (ASPREE) Trial recruited 19,114 participants across Australia and the United States during 2010-2014. Participants were randomized to receive either 100 mg of aspirin daily or matching placebo, with disability-free survival as the primary outcome. During a median 4.7 years of follow-up, 37% of participants in the aspirin group permanently ceased taking their study medication and 10% commenced open-label aspirin use. In the placebo group, 35% and 11% ceased using study medication and commenced open-label aspirin use, respectively. In order to estimate compliance-adjusted effects of aspirin, we applied rank-preserving structural failure time models. The results for disability-free survival and most secondary endpoints were similar in intention-to-treat and compliance-adjusted analyses. For major hemorrhage, cancer mortality, and all-cause mortality, compliance-adjusted effects of aspirin indicated greater risks than were seen in intention-to-treat analyses. These findings were robust in a range of sensitivity analyses. In accordance with the original trial analyses, compliance-adjusted results showed an absence of benefit with aspirin for primary prevention in older people, along with an elevated risk of clinically significant bleeding.

What type of exercise is most effective for people with knee osteoarthritis and co-morbid obesity?: The TARGET randomized controlled trial.

OBJECTIVE: Different exercise types may yield different outcomes in osteoarthritis (OA) subgroups. The objective was to directly compare effectiveness of two exercise programs for people with medial knee OA and co-morbid obesity. DESIGN: We performed a participant- and assessor-blinded randomized controlled trial. 128 people ≥50 years with medial knee OA and body mass index ≥30 kg/m2 were recruited from the community. Interventions were home-based non-weight bearing (NWB) quadriceps strengthening or weight bearing (WB) functional exercise for 12 weeks. Primary outcomes were change in overall knee pain (numeric rating scale, range 0-10) and difficulty with physical function (Western Ontario and McMaster Universities Osteoarthritis Index, 0-68) over 12 weeks. Secondary outcomes included other pain measures, physical function, quality-of-life, global changes, physical performance, and lower-limb muscle strength. RESULTS: 123 (96%) participants were retained. There was no evidence of a between-group difference in change in pain (mean difference 0.73 units (95% confidence intervals (0.05,1.50)) or function (2.80 units (-1.17,6.76)), with both groups reporting improvements. For secondary outcomes, the WB group had greater improvement in quality-of-life (-0.043 units (-0.085,-0.001)) and more participants reporting global improvement (overall: relative risk 1.40 (0.98,2.01); pain 1.47 (0.97,2.24); function 1.43 (1.04,1.98). Although adverse events were minor, more NWB group participants reported ≥1 adverse event (26/66 (39%) vs 14/62 (23%), p = 0.04). CONCLUSIONS: Both exercise types similarly improved primary outcomes of pain and function and can be recommended for people with knee OA and obesity. WB exercise may be preferred given fewer adverse events and potential additional benefits on some secondary outcomes. REGISTRATION: Prospectively registered (Australian New Zealand Clinical Trials Registry #12617001013358, 14/7/2017).

A population-based epidemiological study of neuromyelitis optica spectrum disorder in Hungary.

BACKGROUND AND PURPOSE: The goal of this study was to determine the prevalence and incidence of neuromyelitis optica spectrum disorder (NMOSD) in Hungary based on the 2015 International Panel of NMO Diagnosis (IPND) criteria. METHODS: A retrospective population-based cohort study was conducted of 6.4 million Hungarians (age ≥ 16 years) between 1 January 2006 and 31 December 2016. Possible NMOSD patients were selected via multistage re-evaluation from multiple sources. Crude and sex- and serostatus-specific prevalence (per 100 000 persons) and incidence rates (per 1 000 000 person-years) from 2006 to 2015 were estimated and age-adjusted rates were determined. RESULTS: Of 2262 study candidates, 154 NMOSD patients (age ≥ 16 years) with onset until 31 December 2016 were identified based on 2015 IPND criteria. The prevalence analysis on 1 January 2016 included 123 NMOSD living cases, resulting in a prevalence of 1.91 [95% confidence interval (CI) 1.52-2.28] per 100 000 persons. The 101 incident cases emerging from the observed 76 394 288 person-years provided an incidence rate of 1.32 (95% CI 1.08-1.61) per 1 000 000 person-years. Age-adjusted prevalence was 1.87 (95% CI 1.56-2.23) per 100 000 persons and incidence was 1.20 (95% CI 0.98-1.46) per 1 000 000 person-years. CONCLUSIONS: In this first report of a large population-based epidemiological study from an Eastern European Caucasian population using robust case validation, a greater prevalence and incidence of NMOSD was found compared to previous large studies in Caucasian populations.

Effect of cane use on bone marrow lesion volume in people with medial tibiofemoral knee osteoarthritis: randomized clinical trial.

OBJECTIVE: To evaluate effects of daily cane use for 3 months on medial tibiofemoral bone marrow lesion (BML) volumes in people with medial tibiofemoral osteoarthritis (OA). DESIGN: In this randomized controlled trial (RCT), 79 participants with medial tibiofemoral OA were randomized to either a cane group (using a cane whenever walking) or control group (not using any gait aid) for 3 months. The cane group received a single training session by a physiotherapist, using a biofeedback cane to teach optimal technique and body weight support and motor learning principles to facilitate retention of learning. The primary outcome was change in total medial tibiofemoral BML volume (per unit bone volume) measured from magnetic resonance imaging (MRI) at 3 months. Secondary outcomes were BML volumes (per unit bone volume) of the medial tibia and femur, and patient-reported outcomes of overall knee pain, knee pain on walking, physical function, perceived global symptom changes and health-related quality of life. MRI analyses were performed by a blinded assessor. RESULTS: Seventy-eight participants (99%) completed the primary outcome. Mean (standard deviation) daily cane use was 2.3 (1.7) hours over 3 months. No evidence of between-group differences was found for change in total medial tibiofemoral BML volume (mean difference: -0.0010 (95% confidence intervals: -0.0022, 0.0003)). Most secondary outcomes showed minimal differences between groups. CONCLUSION: Daily use of a cane during walking for 3 months aiming to reduce knee joint loading did not change medial tibiofemoral BML volumes compared to no use of gait aids. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ACTRN12614000909628).

Trajectories of adherence to home-based exercise programs among people with knee osteoarthritis.

OBJECTIVE: To investigate the presence of different trajectories of self-reported adherence to home exercise programs among people with knee osteoarthritis (OA), and to compare baseline characteristics across identified groups. DESIGN: Pooled analysis of data from three randomised controlled trials involving exercise interventions for people aged ≥50 years with clinical knee OA (n = 341). Exercise adherence was self-reported on an 11-point numerical rating scale (NRS; 0 = not at all-10 = completely as instructed). Latent class growth analysis was used to identify distinct trajectories of adherence, at intervals from 12 to 78 weeks from baseline. Baseline characteristics of these groups were compared using chi-squared tests, one-way analysis of variance (ANOVA) and Kruskal Wallis tests where appropriate. RESULTS: Three distinct adherence trajectories were identified: a "Rapidly declining adherence" group (n = 157, 47.4%) whose adherence was 7.7 ± 1.6 (/10) at 12 weeks, declined to 4.2 ± 2.2 by 22 weeks and remained low thereafter; a "Gradually declining adherence" group (n = 153, 45.1%) whose adherence declined from 8.5 ± 1.5 to 7.8 ± 1.5 over the same period, and continued to decline slowly, and a "Low adherence" group (n = 21, 6.3%) whose adherence was 2.2 ± 1.4 at 12 weeks and remained low. At baseline the "Rapidly declining adherence" group reported significantly lower Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (mean difference (95% Confidence Interval (CI)) -0.8 (-1.4, -0.2)) and better WOMAC function compared to the "Gradually declining adherence" group (-3.1 (-5.2, -1.1)). CONCLUSION: Three trajectories of self-reported adherence to home exercises were found among people with knee OA. Findings highlight the need for close monitoring of adherence from initiation of a home exercise program in order to identify and intervene when low or rapidly declining adherence is identified.

Knee extensor strength gains mediate symptom improvement in knee osteoarthritis: secondary analysis of a randomised controlled trial.

OBJECTIVE: To determine if an increase in knee extensor strength mediates the effect of a 12-week knee extensor strength training program on pain and physical function improvement in people with knee osteoarthritis (OA). DESIGN: Secondary analysis from a randomised controlled trial comparing the effects of a 12-week knee extensor strengthening exercise program to a control group with no intervention. METHODS: Data from participants with complete data (n = 97) enrolled in a previous clinical trial were analysed. Baseline and 12-week follow-up assessments included peak isometric knee extensor strength, pain and physical function. Peak knee extensor strength (Nm/kg) was assessed on an isokinetic dynamometer and subscales of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index were used to assess pain and physical function. Twelve-week change in pain and physical function were regressed separately, on 12-week change in knee extensor strength and group allocation. Covariates included baseline pain or physical function as appropriate, and baseline knee extensor strength, age, sex and knee alignment (stratification variable). RESULTS: Improved knee extensor strength mediated the effect of the strengthening program on both pain relief (mediated effect size = 0.69, 95% confidence intervals (CI) 0.05-1.33, P = 0.03), and improved physical function (mediated effect size = 1.86, 95% CI 0.08-3.64, P = 0.04), at 12 weeks. CONCLUSIONS: Increased knee extensor strength partially mediates the effect of a knee extensor strength training program on pain and physical function improvement in people with knee OA.

Moderators and mediators of effects of unloading shoes on knee pain in people with knee osteoarthritis: an exploratory analysis of the SHARK randomised controlled trial.

OBJECTIVE: To investigate moderators and biomechanical mediators of effects of unloading shoes on knee pain in people with knee osteoarthritis (OA). METHODS: Exploratory analysis from 164 participants in a clinical trial comparing unloading (ASICS GEL-Melbourne OA) to conventional walking shoes. The primary outcome was 6-month change in knee pain (11-point numerical rating scale (NRS)). Moderators included baseline peak knee adduction moment (KAM), radiographic severity (Kellgren & Lawrence (KL) scale), body mass, foot posture, neuropathic pain and diffuse knee pain. Mediators included change in peak KAM and KAM impulse. RESULTS: Radiographic severity was the only moderator to interact with footwear group (P = 0.02). Participants with KL = 2 experienced greater pain reductions with conventional compared to unloading shoes (mean difference in change in pain -1.64 units, 95% CI -3.07, -0.21), while unloading shoes tended to result in greater pain reductions than conventional shoes in KL = 3 (0.98, 95% CI -0.44, 2.39) and KL = 4 (0.64, 95% CI -0.64, 1.93). No variable showed any significant mediating effect in the entire cohort. However, there was some evidence that unloading shoes may reduce pain through reductions in peak KAM (indirect effect -0.31, 95% CIs -0.65, 0.03; P = 0.07) in people with KL ≥ 3, compared to conventional shoes. CONCLUSION: Unloading shoes conferred additional symptomatic benefits over conventional shoes in people with moderate to severe knee OA. There was some evidence effects may be mediated by a reduction in peak KAM. However, we were underpowered for subgroup analyses. These patients may represent a subgroup to which biomechanical interventions designed to reduce the KAM may be more effectively targeted.

Correction to: Effectiveness of a new model of primary care management on knee pain and function in patients with knee osteoarthritis: Protocol for THE PARTNER STUDY.

After the publication of this protocol [1], our collaborator Prima Health solutions advised us of their intent to withdraw from the study.

Longitudinal association between foot and ankle symptoms and worsening of symptomatic radiographic knee osteoarthritis: data from the osteoarthritis initiative.

OBJECTIVE: To assess whether foot and/or ankle symptoms are associated with an increased risk of worsening of knee pain and radiographic change in people with knee osteoarthritis (OA). METHODS: The presence and laterality of foot/ankle symptoms were recorded at baseline in 1368 participants from the Osteoarthritis Initiative (OAI) with symptomatic radiographic knee OA. Knee pain severity (measured using the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale) and minimum medial tibiofemoral joint space (minJSW) width measured on X-ray were assessed yearly over the subsequent 4 years. Associations between foot/ankle symptoms and worsening of (1) knee pain, and (2) both knee pain and minJSW (i.e., symptomatic radiographic knee OA) were assessed using logistic regression. RESULTS: Foot/ankle symptoms in either foot/ankle significantly increased the odds of knee pain worsening (adjusted OR 1.54, 95% CI 1.25 to 1.91). Laterality analysis showed ipsilateral (adjusted OR 1.50, 95% CI 1.07 to 2.10), contralateral (adjusted OR 1.44, 95% CI 1.02 to 2.06) and bilateral foot/ankle symptoms (adjusted OR 1.61, 95% CI 1.22 to 2.13) were all associated with knee pain worsening in the follow up period. There was no association between foot/ankle symptoms and worsening of symptomatic radiographic knee OA. CONCLUSION: The presence of foot/ankle symptoms in people with symptomatic radiographic knee OA was associated with increased risk of knee pain worsening, but not worsening of symptomatic radiographic knee OA, over the subsequent 4 years. Future studies should investigate whether treatment of foot/ankle symptoms reduces the risk of knee pain worsening in people with knee OA.

The relationship between foot and ankle symptoms and risk of developing knee osteoarthritis: data from the osteoarthritis initiative.

OBJECTIVE: To investigate whether foot and/or ankle symptoms increase the risk of developing (1) knee symptoms and (2) symptomatic radiographic knee osteoarthritis (OA). DESIGN: 1020 Osteoarthritis Initiative (OAI) participants who were at-risk of knee OA, but were without knee symptoms or radiographic knee OA, were investigated. Participants indicated the presence and laterality of foot/ankle symptoms at baseline. The main outcome was development of knee symptoms (pain, aching or stiffness in and around the knee on most days of the month for at least 1 month in the past year). A secondary outcome was development of symptomatic radiographic knee OA (symptoms plus Kellgren and Lawrence [KL] grade ≥2), over the subsequent 4 years. Associations between foot/ankle symptoms and study outcomes were assessed by logistic regression models. RESULTS: Foot/ankle symptoms in either or both feet significantly increased the odds of developing knee symptoms (adjusted odds ratio (OR) 1.55, 95% confidence interval (CI) 1.10 to 2.19), and developing symptomatic radiographic knee OA (adjusted OR 3.28, 95% CI 1.69 to 6.37). Based on laterality, contralateral foot/ankle symptoms were associated with developing both knee symptoms (adjusted OR 1.68, 95% CI 1.05 to 2.68) and symptomatic radiographic knee OA (adjusted OR 3.08, 95% CI 1.06 to 8.98), whilst bilateral foot/ankle symptoms were associated with developing symptomatic radiographic knee OA (adjusted OR 4.02, 95% CI 1.76 to 9.17). CONCLUSION: In individuals at-risk of knee OA, the presence of contralateral foot/ankle symptoms in particular increases risk of developing both knee symptoms and symptomatic radiographic knee OA.

Effects of footwear on the knee adduction moment in medial knee osteoarthritis: classification criteria for flat flexible vs stable supportive shoes.

OBJECTIVE: To validate simple criteria that distinguish flat flexible from stable supportive walking shoes by comparing their effects on the knee adduction moment (KAM) in people with medial knee osteoarthritis (OA). DESIGN: This was a cross-sectional biomechanical study. We proposed five criteria to differentiate flat flexible from stable supportive shoes, and selected three pairs of shoes representing each class for biomechanical testing. 28 participants aged ≥50 years with symptomatic medial knee OA underwent gait analysis barefoot and wearing each of the six selected shoes, in random order. Differences in the peak KAM, KAM impulse and peak knee flexion moment (KFM) across test conditions were evaluated with a two-way repeated measures analysis of variance (ANOVA). Immediate changes in walking pain between conditions were also compared. RESULTS: Increases in KAM from barefoot were lower with each of the three flat flexible shoe styles (peak KAM: 6.1-8.9%; KAM impulse: 2.4-5.1%) compared to their stable supportive counterparts (peak KAM: 11.6-15.1%; KAM impulse 10.5-13.2%). There was a significant main effect for footwear class on peak KAM and KAM impulse, whereby stable supportive shoes increased the KAM significantly more than flat flexible shoes (P < 0.001). There were no differences in the KFM or immediate walking pain between footwear classes. CONCLUSIONS: Our proposed criteria can be used by researchers and clinicians to select flat flexible shoes for people with medial knee OA to minimise knee loading. Future research should evaluate whether wearing shoes based on these criteria translates to improvements in knee OA symptoms and/or slows structural disease progression.

The knee adduction moment and knee osteoarthritis symptoms: relationships according to radiographic disease severity.

OBJECTIVE: To investigate relationships between external knee adduction moment parameters (KAM) and osteoarthritis (OA) symptoms according to disease severity. DESIGN: 164 participants with symptomatic medial knee OA were included. Radiographic severity was graded by (1) Kellgren & Lawrence (KL) scale (Grade 2, n = 49; Grade, n = 52; Grade 4, n = 63) and; (2) medial tibiofemoral joint space narrowing (JSN) (Grade 1, n = 47; Grade 2, n = 50; Grade 3, n = 67). KAM-related parameters (peak KAM, KAM impulse and cumulative load) were determined from three-dimensional gait analysis and pedometry. Cumulative load was determined by multiplying KAM impulse by the average number of steps/day recorded over at least 5 days. Symptoms were assessed via numeric rating scale ((NRS), pain) and Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (pain and physical function). Relationships between KAM parameters (independent variables) and symptoms (dependent variables) were evaluated by radiographic severity using linear models, adjusting for covariates. RESULTS: In mild disease (either KL Grade 2 or JSN Grade 1), there were no associations between KAM and symptoms. In moderate disease of KL Grade 3, higher KAM impulse was associated with greater WOMAC pain. In severe disease (KL Grade 4), higher KAM impulse was associated with less WOMAC pain (KL Grade 4), while higher peak KAM was associated with better function (KL Grade 4). Higher cumulative knee adduction load was associated with less pain on both NRS and WOMAC (JSN Grade 3) as well as better function (both JSN Grade 3 and KL Grade 4). CONCLUSIONS: Relationships between KAM-related parameters and symptoms differ according to underlying radiographic OA severity.

Associations between changes in knee pain location and clinical symptoms in people with medial knee osteoarthritis using footwear for self-management: an exploratory study.

OBJECTIVE: To examine whether change in pain location is associated with clinically-relevant improvements in walking pain severity and physical dysfunction in people with medial tibiofemoral osteoarthritis (OA) using footwear for self-management. DESIGN: We analysed a sub-set of 91 participants pooled from both arms of a 6-month randomised controlled trial of footwear for knee OA. The Photographic Knee Pain Map was self-administered to generate changes in the number of painful zones ('unchanged', 'increased', 'decreased') and anatomical patterns of pain ('unchanged', 'no longer diffuse', 'becoming diffuse', 'other pattern changes'). Improvement in symptoms was determined using the minimum clinically important differences (MCIDs) in pain severity on a numeric rating scale, and function with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Fisher's exact tests examined differences in symptom improvement across categories of change and odds ratios (ORs, 95% CI) were calculated (adjusted for treatment allocation). RESULTS: Seventy-four percent (n = 67) of participants reported a change in pain location, and 46-50% (n = 42-45) reported clinically-relevant improvements in pain and function respectively. Fewer participants 'becoming diffuse' reported improved pain (n = 0, 0%) when compared to the other pattern change categories (P = 0.012). Participants with 'no longer diffuse' (OR (95% CI) = 0.3 (0.1-0.9) or 'becoming diffuse' (OR (95% CI) = 0.0 (0.0-0.4) pain patterns had significantly lower odds of improved function than those with 'other pattern changes'. CONCLUSION: Participants either developing into, or changing from, diffuse pain patterns were less likely to experience improvement in pain and/or function when self-managing with footwear.

Intraoperative dexamethasone does not increase the risk of postoperative wound infection: a propensity score-matched post hoc analysis of the ENIGMA-II trial (EnDEX).

BACKGROUND: In a post hoc analysis of the ENIGMA-II trial, we sought to determine whether intraoperative dexamethasone was associated with adverse safety outcomes. METHODS: Inverse probability weighting with estimated propensity scores was used to determine the association of dexamethasone administration with postoperative infection, quality of recovery, and adverse safety outcomes for 5499 of the 7112 non-cardiac surgery subjects enrolled in ENIGMA-II. RESULTS: Dexamethasone was administered to 2178 (40%) of the 5499 subjects included in this analysis and was not associated with wound infection [189 (8.7%) vs 275 (8.3%); propensity score-adjusted relative risk (RR) 1.10; 95% confidence interval (CI) 0.89-1.34; P=0.38], severe postoperative nausea and vomiting on day 1 [242 (7.3%) vs 189 (8.7%); propensity score-adjusted RR 1.06; 95% CI 0.86-1.30; P=0.59], quality of recovery score [median 14, interquartile range (IQR) 12-15, vs median 14, IQR 12-16, P=0.10), length of stay in the postanaesthesia care unit [propensity score-adjusted median (IQR) 2.0 (1.3, 2.9) vs 1.9 (1.3, 3.1), P=0.60], or the primary outcome of the main trial. Dexamethasone administration was associated with a decrease in fever on days 1-3 [182 (8.4%) vs 488 (14.7%); RR 0.61; 95% CI 0.5-0.74; P<0.001] and shorter lengths of stay in hospital [propensity score-adjusted median (IQR) 5.0 (2.9, 8.2) vs 5.3 (3.1, 9.1), P<0.001]. Neither diabetes mellitus nor surgical wound contamination status altered these outcomes. CONCLUSION: Dexamethasone administration to high-risk non-cardiac surgical patients did not increase the risk of postoperative wound infection or other adverse events up to day 30, and appears to be safe in patients either with or without diabetes mellitus. CLINICAL TRIAL REGISTRATION: NCT00430989.

Safety of sedation for gastrointestinal endoscopy in a group of university-affiliated hospitals: a prospective cohort study.

BACKGROUND: Service models for gastrointestinal endoscopy sedation must be safe, as endoscopy is the most common procedure performed under sedation in many countries. The aim of this prospective cohort study was to determine the patient risk profile, and incidence of and risk factors for significant unplanned events, in adult patients presenting for gastrointestinal endoscopy in a group of university-affiliated hospitals where most sedation is managed by anaesthetists. METHODS: Patients aged ≥18 yr presenting for elective and emergency gastrointestinal endoscopy under anaesthetist-managed sedation at nine hospitals affiliated with the University of Melbourne, Australia, were included. Outcomes included significant airway obstruction, hypoxia, hypotension and bradycardia; unplanned tracheal intubation; abandoned procedure; advanced life support; prolonged post-procedure stay; unplanned over-night admission and 30-day mortality. RESULTS: 2,132 patients were included. Fifty percent of patients were aged >60 yr, 50% had a BMI >27 kg m -2, 42% were ASA physical status III-V and 17% were emergency patients. The incidence of significant unplanned events was 23.0% (including significant hypotension 11.8%). Significant unplanned intraoperative events were associated with increasing age, BMI <18.5 kg m -2, ASA physical status III-V, colonoscopy and planned tracheal intubation. Thirty-day mortality was 1.2% (0.2% in electives and 6.0% in emergencies) and was associated with ASA physical status IV-V and emergency status. CONCLUSIONS: Patients presenting for gastrointestinal endoscopy at a group of public university-affiliated hospitals where most sedation is managed by anaesthetists, had a high risk profile and a substantial incidence of significant unplanned intraoperative events and 30-day mortality.

Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial.

BACKGROUND: Previous animal and clinical studies showed that nitrous oxide may produce long-term analgesia. The aim of this study was to evaluate the effect of nitrous oxide in preventing chronic postsurgical pain. We also explored whether methylenetetrahydrofolate reductase gene polymorphisms (1298A>C, 667C>T) would enhance nitrous oxide analgesia. METHODS: We conducted a telephone interview at 12 months after surgery on 2924 (41.1%) patients enrolled in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia-II trial. Pain at the wound site was recorded using the modified brief pain inventory and the neuropathic pain questionnaire. General health status was measured using the EQ-5D questionnaire. Genotyping was performed in a subset of 674 Asian patients in Hong Kong. RESULTS: At 12 months after surgery, 356 (12.2%) patients reported chronic postsurgical pain at the wound site and 112 (3.8%) patients had severe pain and required regular analgesic interventions. Nitrous oxide did not affect the rate of chronic postsurgical pain (11.8% nitrous oxide group; 12.5% no nitrous oxide group), relative risk (95% confidence intervals): 0.94 (0.75-1.17), P=0.57. However, in a planned subgroup analysis, nitrous oxide reduced the risk of chronic postsurgical pain in Asian patients, relative risk (95% confidence intervals): 0.70 (0.50-0.98), P=0.031. Patients who were homozygous for either gene polymorphism and who received nitrous oxide during surgery were less likely to report chronic postsurgical pain. CONCLUSIONS: Nitrous oxide administration had no impact on chronic postsurgical pain, but benefits may still be possible in Asian patients and patients with variants in methylenetetrahydrofolate reductase gene. CLINICAL TRIAL REGISTRATION: NCT00430989.

Neuraxial block and postoperative epidural analgesia: effects on outcomes in the POISE-2 trial†.

BACKGROUND: We assessed associations between intraoperative neuraxial block and postoperative epidural analgesia, and a composite primary outcome of death or non-fatal myocardial infarction, at 30 days post-randomization in POISE-2 Trial subjects. METHODS: 10 010 high-risk noncardiac surgical patients were randomized aspirin or placebo and clonidine or placebo. Neuraxial block was defined as intraoperative spinal anaesthesia, or thoracic or lumbar epidural anaesthesia. Postoperative epidural analgesia was defined as postoperative epidural local anaesthetic and/or opioid administration. We used logistic regression with weighting using estimated propensity scores. RESULTS: Neuraxial block was not associated with the primary outcome [7.5% vs 6.5%; odds ratio (OR), 0.89; 95% CI (confidence interval), 0.73-1.08; P=0.24], death (1.0% vs 1.4%; OR, 0.84; 95% CI, 0.53-1.35; P=0.48), myocardial infarction (6.9% vs 5.5%; OR, 0.91; 95% CI, 0.74-1.12; P=0.36) or stroke (0.3% vs 0.4%; OR, 1.05; 95% CI, 0.44-2.49; P=0.91). Neuraxial block was associated with less clinically important hypotension (39% vs 46%; OR, 0.90; 95% CI, 0.81-1.00; P=0.04). Postoperative epidural analgesia was not associated with the primary outcome (11.8% vs 6.2%; OR, 1.48; 95% CI, 0.89-2.48; P=0.13), death (1.3% vs 0.8%; OR, 0.84; 95% CI, 0.35-1.99; P=0.68], myocardial infarction (11.0% vs 5.7%; OR, 1.53; 95% CI, 0.90-2.61; P=0.11], stroke (0.4% vs 0.4%; OR, 0.65; 95% CI, 0.18-2.32; P=0.50] or clinically important hypotension (63% vs 36%; OR, 1.40; 95% CI, 0.95-2.09; P=0.09). CONCLUSIONS: Neuraxial block and postoperative epidural analgesia were not associated with adverse cardiovascular outcomes among POISE-2 subjects.

Evaluating the performance of Australian and New Zealand intensive care units in 2009 and 2010.

The Australian and New Zealand Intensive Care Society Adult Patient Database (ANZICS APD) is one of the largest databases of its kind in the world and collects individual admissions' data from intensive care units (ICUs) around Australia and New Zealand. Use of this database for monitoring and comparing the performance of ICUs, quantified by the standardised mortality ratio, poses several theoretical and computational challenges, which are addressed in this paper. In particular, the expected number of deaths must be appropriately estimated, the ICU casemix adjustment must be adequate, statistical variation must be fully accounted for, and appropriate adjustment for multiple comparisons must be made. Typically, one or more of these issues have been neglected in ICU comparison studies. Our approach to the analysis proceeds by fitting a random coefficient hierarchical logistic regression model for the inhospital death of each patient, with patients clustered within ICUs. We anticipate the majority of ICUs will be estimated as performing 'usually' after adjusting for important clinical covariates. We take as a starting point the ideas in Ohlssen et al and estimate an appropriate null model that we expect these ICUs to follow, taking a frequentist rather than a Bayesian approach. This methodology allows us to rigorously account for the aforementioned statistical issues and to determine if there are any ICUs contributing to the Australian and New Zealand Intensive Care Society database that have comparatively unusual performance. In addition to investigating the yearly performance of the ICUs, we also estimate changes in individual ICU performance between 2009 and 2010 by adjusting for regression-to-the-mean.

The influence of sex and pre-operative obesity on biomechanics two years after total knee arthroplasty: A longitudinal cohort study.

BACKGROUND: Sex and obesity may influence knee biomechanics associated with poor outcomes following primary total knee arthroplasty (TKA) however their long-term impact has not been investigated. RESEARCH QUESTION: Does sex and/or pre-operative obesity influence change in gait biomechanics from pre-TKA to two-years after TKA, and do knee biomechanics return to normal two-years after TKA? METHODS: In this longitudinal study, gait analysis was performed on 78 patients undergoing TKA for knee osteoarthritis prior to surgery (baseline), and on 66 (85 %) of these who returned at the two year follow-up. Gait biomechanics were also collected on a reference sample of 40 asymptomatic participants. Knee variables were analyzed according to time (pre- and post-TKA), sex (men and women), pre-operative obesity (obese vs non-obese), and group (TKA vs reference). Mixed linear regression models were used to examine the effects of TKA, obesity status, gender and all interactions. RESULTS: There were two-year reductions in peak knee frontal plane angle (mean difference -7.21°; 95% confidence intervals -9.37 to -5.05), peak knee adduction moment (KAM) (-17.64Nm; -23.04 to -12.24) and KAM impulse (-9.40Nm.s; -12.04 to -6.77) in males. These and other variables were unchanged in women. At two years, men exhibited a greater varus-valgus thrust excursion (4.9°; 2.7-7.2), and a lower peak knee frontal plane angle (-4.4°; -7.1 to -1.7) and peak KAM (-13.1Nm; -20.9 to -5.4), compared to the reference sample. Biomechanics at two years did not differ between pre-operative obesity subgroups, or between female TKA patients and the reference sample. SIGNIFICANCE: Changes in gait biomechanics two years after TKA are influenced by sex but not obesity. Men but not women showed altered knee biomechanics two years following TKR and compared to a reference sample. It is unknown whether these altered biomechanics in men impact longer term clinical outcomes and satisfaction following surgery.