Weight Loss for Patients With Gout and Concomitant Obesity: A Proof-of-Concept Randomized Trial.

OBJECTIVE: Despite scarce evidence, guidelines recommend weight loss as a management strategy for patients with gout. We investigated the effect of an intensive dietary intervention on body weight and clinical measures of gout severity in individuals with obesity and gout. METHODS: We conducted a 16-week randomized nonmasked parallel-group trial in Denmark, randomly assigning (one-to-one) individuals with obesity and gout to a low-energy diet or a control diet. The primary outcome was change in body weight. Key secondary outcomes were changes in serum urate (SU) level and visual analog scale-assessed pain and fatigue. RESULTS: Between December 1, 2018, and June 1, 2019, 61 participants were included in the intention-to-treat population and randomly assigned to the intensive diet group (n = 29) or control diet group (n = 32). Participants had a mean age of 60.3 (SD 9.9) years and mean body mass index of 35.6 (SD 5.0), and 59 (97%) were men. After 16 weeks, there was a significant difference in change in body weight between the diet and control groups (-15.4 vs -7.7 kg; difference -7.7 kg [95% confidence interval -10.7 to -4.7], P < 0.001). Despite results being potentially in favor of a low-energy diet, we could not confirm differences in SU level changes and fatigue between groups. No differences in pain and gout flares were observed between groups. No serious adverse events or deaths occurred during the trial. CONCLUSION: An intensive dietary intervention was safe and effectively lowered body weight in people with obesity and gout, but the weight loss did not directly translate into effects on SU level, fatigue, and pain.

Changes in physical activity during a one-year weight loss trial with liraglutide vs placebo in participants with knee osteoarthritis: Secondary analyses of a randomised controlled trial.

Objective: To assess if a change in physical activity occurred after a one-year weight loss period on either liraglutide or placebo in patients with knee osteoarthritis (OA) and overweight. Method: This is secondary analysis of a one-year weight loss trial, with participants randomised (1:1) to either liraglutide 3 â€‹mg/day or placebo. The main outcome was change in physical activity (min/day) after one year assessed by accelerometer. Physical function was assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS), function subscale with 100 indicating no disability and 0 indicating extreme disability. Analyses were done on the modified intention to treat population defined as complete baseline accelerometer data. Results: A total of 135 participants were analysed (66 liraglutide; 69 placebo). Daily physical activity time did not change in either group (liraglutide: 15.8 â€‹min/day; placebo: 14.2 â€‹min/day; mean difference 1.6 â€‹min/day (95%CI -16 to 19; P â€‹= â€‹0.90)). The liraglutide group lost -4.1 â€‹kg more than placebo (95% CI -6.0 to -2.1; P â€‹< â€‹0.0001) and improved in KOOS function 3.8 points more than placebo (95% CI 0.9 to 6.7; P â€‹= â€‹0.01). Conclusion: Despite better outcomes on body weight and self-reported physical functioning liraglutide did not induce changes in physical activity over one year in individuals with knee OA.

Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial.

OBJECTIVE: To compare the efficacy of an exercise and education programme with open-label placebo given as intra-articular injections of inert saline on pain and function in individuals with knee osteoarthritis (OA). METHODS: In this open-label, randomised controlled trial, we recruited adults aged ≥50 years with symptomatic and radiographically confirmed knee OA in Denmark. Participants were randomised 1:1 to undergo an 8-week exercise and education programme or four intra-articular saline injections over 8 weeks. Primary outcome was change from baseline to week 9 in the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire pain subscale (range 0 (worst)-100 (best)). Prespecified equivalence margins of ±8 KOOS pain points were chosen for the demonstration of comparable efficacy. Key secondary outcomes were the KOOS function and quality of life subscales, and patients' global assessment of disease impact. RESULTS: 206 adults were randomly assigned: 102 to exercise and education and 104 to intra-articular saline injections. For the primary outcome, the least squares mean changes in KOOS pain were 10.0 for exercise and education and 7.3 for saline injections (difference 2.7 points, 95% CI -0.6 to 6.0; test for equivalence p=0.0008). All group differences in the key secondary outcomes respected the predefined equivalence margins. Adverse events and serious adverse events were similar in the two groups. CONCLUSION: In individuals with knee OA, an 8-week exercise and education programme provided efficacy for symptomatic and functional improvements equivalent to that of four open-label intra-articular saline injections over 8 weeks. TRIAL REGISTRATION NUMBER: NCT03843931.

Exercise therapy and patient education versus intra-articular saline injections in the treatment of knee osteoarthritis: an evidence-based protocol for an open-label randomised controlled trial (the DISCO trial).

BACKGROUND: Knee osteoarthritis (OA) is a highly prevalent musculoskeletal condition causing pain, physical disability, and reduced quality of life. Exercise and patient education are non-pharmacological interventions for knee OA unanimously recommended as first-line treatments based on extensive research evidence. However, none of the numerous randomised controlled trials of exercise and education for knee OA has used adequate sham/placebo comparison groups because the 'active' ingredients are unknown. Designing and executing an adequate and 'blindable placebo' version of an exercise and education intervention is impossible. Therefore, using an open-label study design, this trial compares the efficacy of a widely used 'state-of-art' exercise and education intervention (Good Life with osteoarthritis in Denmark; GLAD) with presumably inert intra-articular saline injections on improvement in knee pain in patients with knee OA. METHODS: In this open-label randomised trial, we will include 200 patients with radiographically verified OA of the knee and randomly allocate them to one of two interventions: (i) 8 weeks of exercise and education (GLAD) or (ii) Intra-articular injections of 5 ml isotonic saline every second week for a total of 4 injections. Outcomes are taken at baseline, after 8 weeks of treatment (week 9; primary endpoint) and after an additional 4 weeks of follow-up (week 12). The primary outcome is change from baseline in the Knee Injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale score. Secondary outcomes include the Physical function in Activities of Daily Living, Symptoms, and Knee-related Quality of Life subscales of the KOOS, the patients' global assessment of disease impact, physical performance tests, and presence of knee joint swelling. DISCUSSION: This current trial compares a presumably active treatment (GLAD) with a presumably inert treatment (IA saline injections). Both study interventions have well-established and anticipated similar effects on knee OA symptoms, but the underlying mechanisms are unknown. The interpretation of the results of this trial will likely be difficult and controversial but will contribute to a better understanding of the bias introduced in the effect estimation of classically unblindable exercise and education interventions for knee OA. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT03843931 . Prospectively registered on 18 February 2019.

Liraglutide after diet-induced weight loss for pain and weight control in knee osteoarthritis: a randomized controlled trial.

BACKGROUND: Weight loss is critical for preventing and managing obesity-related diseases. There is a notable lack of valid and reliable means to manage patients with overweight/obesity and knee osteoarthritis (KOA). OBJECTIVE: To determine the efficacy and safety of liraglutide in a 30 mg/d dosing in patients with overweight/obesity and KOA. METHODS: The trial was designed as a randomized controlled trial including patients between the age of 18 and 74 y with KOA and a BMI ≥27 (measured in kg/m2).Patients underwent a pre-random assignment diet intervention (week -8 to 0). At week 0, patients having lost >5% of their body weight were randomly assigned to liraglutide 3 mg/d or placebo for 52 wk. The coprimary outcomes were changes in body weight and the Knee injury and Osteoarthritis Outcome Score (KOOS) pain subscale from week 0 to 52. RESULTS: In total, 168 patients enrolled and 156 were randomly assigned to receive liraglutide or placebo. Patients experienced a significant reduction in body weight and KOOS pain during the pre-random assignment dietary intervention period (week -8 to 0). From week 0 to 52 there was a significant difference in body weight between the liraglutide and placebo group (mean changes: -2.8 and +1.2 kg, respectively; group difference, 3.9 kg; 95% CI: -6.9, -1.0; P = 0.008). There was, however, no group difference in KOOS pain (mean changes: 0.4 and -0.6 points, respectively; group difference, 0.9 points; 95% CI: -3.9, 5.7; P = 0.71). Treatment-emergent adverse events related to the gastrointestinal system were experienced by 50.2% and 39.2% of patients in the liraglutide and placebo groups, respectively. CONCLUSIONS: In patients with KOA and overweight/obesity liraglutide added after an 8-wk pre-random assignment diet induced a significant weight loss at >52 wk but did not reduce knee pain compared to placebo. This trial was registered at clinicaltrials.gov as NCT02905864.

The implications of an aging population and increased obesity for knee arthroplasty rates in Sweden: a register-based study.

Background and purpose - Total knee arthroplasty (TKA) has increased substantially in Sweden. We quantified the relative risk for TKA in the Swedish population for different BMI categories and age groups to investigate whether the continued increase in TKA is attributable to increased prevalence of obesity and elderly people in the population, and to put forward model predictions for coming needs for TKA. Patients and methods - We used the Swedish Nationwide Health Survey (SNHS) and the Swedish Knee Arthroplasty Register (SKAR) 2009-2015 to calculate the relative risk (RR) of TKA by age (middle-aged 45-64 years and elderly 65-84 years) and BMI (BMI 18.5-24.9 normal weight; BMI 25.0-29.9 overweight; BMI > 30 obese). The RR for TKA was applied to the demographic forecasts for the Swedish population as a forecasting model. Results - Population size increased 5.2% from 2009 to 2015 to 40,000 middle-aged and 250,000 elderly, and the prevalence of obesity increased from 16% to 18% in these 2 age categories. Compared with those of normal weight, the RR for TKA was 2.7 (95% CI 2.5-3.0) higher for the overweight and 7.3 (6.7-8.0) higher for the obese, aged 45-64. The corresponding figures for individuals aged 65-84 were 2.1 (2.0-2.2) and 4.0 (3.8-4.3) higher, respectively. The changes in the prevalence of obesity and an increase in the elderly population accounted for an estimated increase of 1,700 TKAs over the 7 years. Interpretation - The increase in obesity frequency and the rise in the population of middle-aged and elderly may, to some extent, explain the rise in TKA utilization in Sweden.

Identifying values and preferences around the choice of analgesia for patients with acute trauma pain in emergency and prehospital settings: using group concept mapping methodology.

OBJECTIVES: The main study aim was to examine the applicability of a novel method to assess the criterion of values and preferences within the Grading of Recommendation, Assessment, Development and Evaluation evidence to decision framework. The group concept mapping (GCM) approach was applied to identify, organise and prioritise values and preferences in the example of health professionals' choice of analgesia for patients with acute trauma pain. SETTING: Prehospital and emergency care centres in the Nordic countries of Denmark, Norway, Sweden, Finland and Iceland. PARTICIPANTS: Acute care health professionals with qualifications to administer analgesic agents to patients in emergency and prehospital settings, including advanced ambulance assistants, rescue officers, paramedics, emergency physicians and emergency nurses, participated in an online survey in which statements were generated (n=40) and structured (n=11) and finally analysed and interpreted in a validation meeting (n=4). RESULTS: Using GCM, ideas were generated and structured through online participation. Results were interpreted at a validation meeting. In total, 111 unique ideas were identified and organised into seven clusters: drug profile, administration, context, health professionals' preferences and logistics, safety profile, patient's medical history and acute clinical situation. CONCLUSIONS: Based on GCM, a conceptual model was developed, and values and preferences around choice of analgesia in emergency care were revealed. Health professionals within acute care can apply the conceptual model to support their decision-making when choosing the best available treatment for pain for their patients in emergency care.

Association Between Weight Loss and Spontaneous Changes in Physical Inactivity in Overweight/Obese Individuals With Knee Osteoarthritis: An Eight-Week Prospective Cohort Study.

OBJECTIVE: To describe spontaneous changes in time spent being physically inactive that is measured continuously by accelerometry during an 8-week weight-loss intervention in overweight/obese individuals with knee osteoarthritis (OA). METHODS: This study was designed as an observational cohort study including individuals from an OA outpatient clinic who were concomitantly overweight/obese and had symptomatic knee OA. Participants completed an 8-week dietary intervention that had been previously shown to induce substantial weight loss. The main outcome was accelerometer-based measurement of daily physical inactivity for 24 hours during the 8-week intervention period that was presented as change in the average daily time spent inactive (sitting, reclined, or sleeping) from 1 week prior to intervention to the last week of the intervention. RESULTS: A total of 124 participants completed the dietary intervention and had valid accelerometer recordings. The mean weight loss was 12.7 kg (95% confidence interval [95% CI] -13.2, -12.1; P < 0.0001) after 8 weeks, which corresponded to a decrease in body mass index of 4.3 kg/m2 (95% CI -4.5, -4.2; P < 0.0001). Significant improvements in OA symptoms (assessed by the Knee Injury and Osteoarthritis Outcome Score [KOOS]) was found across all subscales; an improvement of 12.8 points (95% CI 10.6, 15.0; P < 0.0001) was observed for pain using the KOOS. No statistically significant change occurred in the average daily time spent inactive from baseline to follow-up (mean change 8.8 minutes/day [95% CI -12.1, 29.7]; P = 0.41). CONCLUSION: Physical inactivity remains stable despite a clinically significant weight loss and improvements in knee OA symptoms. Change in inactivity does not seem to occur spontaneously, suggesting that focused efforts to reduce inactive behaviors are needed.

Effect of liraglutide on body weight and pain in patients with overweight and knee osteoarthritis: protocol for a randomised, double-blind, placebo-controlled, parallel-group, single-centre trial.

INTRODUCTION: With an increasing prevalence of citizens of older age and with overweight, the health issues related to knee osteoarthritis (OA) will intensify. Weight loss is considered a primary management strategy in patients with concomitant overweight and knee OA. However, there are no widely available and feasible methods to sustain weight loss in patients with overweight and knee OA. The present protocol describes a randomised controlled trial evaluating the efficacy and safety of the glucagon-like peptide-1 receptor agonist liraglutide in a 3 mg/day dosing in patients with overweight and knee OA. METHODS AND ANALYSIS: 150 volunteer adult patients with overweight or obesity and knee OA will participate in a randomised, double-blind, placebo-controlled, parallel-group and single-centre trial. The participants will partake in a run-in diet intervention phase (week -8 to 0) including a low calorie diet and dietetic counselling. At week 0, patients will be randomised to either liraglutide 3 mg/day or liraglutide placebo 3 mg/day for 52 weeks as an add-on to dietetic guidance on re-introducing regular foods and a focus on continued motivation to engage in a healthy lifestyle. The co-primary outcomes are changes in body weight and the Knee Injury and Osteoarthritis Outcome Score pain subscale from week 0 to week 52. ETHICS AND DISSEMINATION: The trial has been approved by the regional ethics committee in the Capital Region of Denmark, the Danish Medicines Agency and the Danish Data Protection Agency. An external monitoring committee (The Good Clinical Practice Unit at Copenhagen University Hospitals) will oversee the trial. The results will be presented at international scientific meetings and through publications in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: 2015-005163-16, NCT02905864, U1111-1171-4970 BASED ON PROTOCOL VERSION: V.6; 30 January 2017, 15:30 hours.

Patient-reported 1-year outcome not affected by body mass index in 3,327 total knee arthroplasty patients.

Background and purpose - Patient-reported outcome (PRO) in total knee arthroplasty (TKA) patients with high body mass index (BMI) is controversial. We compared pain, function, quality of life, general health, and satisfaction among different BMI categories preoperatively and 1 year after primary TKA. Patients and methods - 4,318 patients were operated with a TKA for knee osteoarthritis in the Region of Skane in 2013-2015. In all, 3,327 patients (77%) had complete PRO data and information on BMI and were included. Preoperatively the patients filled in the Knee injury and Osteoarthritis Outcome Score (KOOS) and EQ-VAS (general health). 1 year postoperatively the same questionnaires were filled in together with a question asking whether they were satisfied with the surgery. Information on age, sex, BMI, and ASA grade were obtained from the Swedish Knee Arthroplasty Register. Each patient was classified as Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT-OARSI) responder or not based on a combination of absolute and relative changes in scores. Welch's t-test and a chi-square test were used in the statistical analysis. Results - Both preoperatively and 1 year postoperatively the obese patients reported somewhat worse scores than the normal weight and overweight. The differences were small with 1 exception, the KOOS sport- and recreation function postoperatively, where normal-weight and overweight patients reported fewer problems than obese patients with a BMI over 35 (40 and 39 points vs. 31 points, p < 0.001). Similar proportions of patients were satisfied and categorized as OMERACT-OARSI responders in the different BMI categories. Interpretation - The degree of improvement in PROs 1 year after TKA surgery does not seem to be affected by BMI.

Intra-articular 2.5% polyacrylamide hydrogel for the treatment of knee osteoarthritis: an observational proof-of-concept cohort study.

OBJECTIVES: There is a drought of effective treatments of knee osteoarthritis (OA) and new therapies are needed. The present study has been conducted to establish an initial estimate of effectiveness of intra-articular (IA) injection of a proprietary 2.5% cross-linked polyacrylamide hydrogel (PAAG) for the treatment of knee OA symptoms and signs. METHODS: Patients with knee OA were invited into a prospective open-label cohort study. The patients received up to two IA injections of 3 ml of PAAG 1 month apart. The WOMAC questionnaire was used to estimate effectiveness, and was collected at baseline and after 4, 7 and 13 months. Primary outcome was change from baseline for the WOMAC pain subscale after 4 months (Normalised to 0-100 points; 100 worst). Data was analysed using a mixed-effect model without imputation of missing data. RESULTS: 84 patients (48 females) received IA PAAG. Of these WOMAC data were available from 62 after 4 months, 59 after 7 months, and 56 after 13 months. There were statistically and clinically significant reductions in WOMAC pain after 4 months (mean change -14.6 points [95% CI: -18.9 to -10.2]; p<.0001). Similar results were found in WOMAC stiffness, physical function, and WOMAC total. The improvement was sustained throughout the observation period. CONCLUSIONS: These results suggest beneficial effects of IA injection of PAAG on knee OA symptoms, even in the long term (1 year). This initial estimation of effectiveness is promising but needs to be confirmed in a randomised study with adequate measures taken to reduce risk of bias.

Reduced cerebral oxygen-carbohydrate index during endotracheal intubation in vascular surgical patients.

Brain activation reduces balance between cerebral consumption of oxygen versus carbohydrate as expressed by the so-called cerebral oxygen-carbohydrate-index (OCI). We evaluated whether preparation for surgery, anaesthesia including tracheal intubation and surgery affect OCI. In patients undergoing aortic surgery, arterial to internal jugular venous (a-v) concentration differences for oxygen versus lactate and glucose were determined from before anaesthesia to when the patient left the recovery room. Intravenous anaesthesia was supplemented with thoracic epidural anaesthesia for open aortic surgery (n = 5) and infiltration with bupivacaine for endovascular procedures (n = 14). The a-v difference for O2 decreased throughout anaesthesia and in the recovery room (1.6 ± 1.9 versus 3.2 ± 0.8 mmol l(-1), mean ± SD), and while a-v glucose decreased during surgery and into the recovery (0.4 ± 0.2 versus 0.7 ± 0.2 mmol l(-1) , P<0.05), a-v lactate did not change significantly (0.03 ± 0.16 versus -0.03 ± 0.09 mmol l(-1)). Thus, OCI decreased from 5.2 ± 1.8 before induction of anaesthesia to 3.2 ± 1.0 following tracheal intubation (P<0.05) because of the decrease in a-v O2 with a recovery for OCI to 4.6 ± 1.4 during surgery and to 5.6 ± 1.7 in the recovery room. In conclusion, preparation for surgery and tracheal intubation decrease OCI that recovers during surgery under the influence of sensory blockade.

Hypercoagulability in response to elevated body temperature and central hypovolemia.

BACKGROUND: Coagulation abnormalities contribute to poor outcomes in critically ill patients. In trauma patients exposed to a hot environment, a systemic inflammatory response syndrome, elevated body temperature, and reduced central blood volume occur in parallel with changes in hemostasis and endothelial damage. The objective of this study was to evaluate whether experimentally elevated body temperature and reduced central blood volume (CBV) per se affects hemostasis and endothelial activation. METHODS: Eleven healthy volunteers were subjected to heat stress, sufficient to elevate core temperature, and progressive reductions in CBV by lower body negative pressure (LBNP). Changes in hemostasis were evaluated by whole blood haemostatic assays, standard hematologic tests and by plasma biomarkers of coagulation and endothelial activation/disruption. RESULTS: Elevated body temperature and decreased CBV resulted in coagulation activation evidenced by shortened activated partial tromboplastin time (-9% [IQR -7; -4]), thrombelastography: reduced reaction time (-15% [-24; -4]) and increased maximum amplitude (+4% (2; 6)), all P < 0.05. Increased fibrinolysis was documented by elevation of D-dimer (+53% (12; 59), P = 0.016). Plasma adrenaline and noradrenaline increased 198% (83; 346) and 234% (174; 363) respectively (P = 0.006 and P = 0.003). CONCLUSIONS: This experiment revealed emerging hypercoagulability in response to elevated body temperature and decreased CBV, whereas no effect on the endothelium was observed. We hypothesize that elevated body temperature and reduced CBV contributes to hypercoagulability, possibly due to moderate sympathetic activation, in critically ill patients and speculate that normalization of body temperature and CBV may attenuate this hypercoagulable response.