AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys.

OBJECTIVES: Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment. METHODS: We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period. RESULTS: AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (P = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (P = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (P = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (P = 0.008), glucose by 30% (P = 0.02), triglycerides by 39% (P = 0.05), total cholesterol by 29% (P = 0.03), and LDL cholesterol by 48% (P = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects. CONCLUSIONS: This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

CONTEXT: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. OBJECTIVE: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. DESIGN, PATIENTS, SETTING, INTERVENTIONS: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. MAIN OUTCOME MEASURE: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. RESULTS: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. CONCLUSIONS: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Midluteal serum estradiol levels are associated with live birth rates in hormone replacement therapy frozen embryo transfer cycles: a cohort study.

OBJECTIVE: To study whether midluteal serum estradiol (E2) levels are associated with the live birth rate in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles in patients with optimal midluteal serum progesterone (P4) levels. DESIGN: Observational prospective cohort study. SETTING: Public fertility clinic. PATIENTS: A total of 412 women had an HRT-FET cycle single blastocyst transfer from January 2020 to November 2022. INTERVENTION: The HRT-FET cycle priming regimen included oral E2 (6mg/24 h) administered in the evening, followed by vaginal P4 (400mg/12 h). Serum E2 and P4 levels were measured using a standardized method, 2-4 hours after the latest P4 administration and 9-14 hours after E4 administration on the day of blastocyst transfer, day 6 of P4 administration. Patients with serum P4 levels (<11 ng/mL [35 nmol/L]) on the day of transfer received additional rectal P4 (400mg/12 h). No additional E2 dose was administered. MAIN OUTCOME MEASURES: The primary outcome was the live birth rate (LBR) in relation to E2 levels at blastocyst transfer day. RESULTS: The optimal serum E2 levels correlating with ongoing pregnancy were ≥292 pg/mL and <409 pg/mL (≥1,070 pmol/L and <1,500 pmol/L). The LBR was 59% (60/102) when E2 levels were within this range, whereas a significantly lower LBR of 39% (101/260) was seen in patients when E2 levels were <292 pg/mL (<1,070 pmol/L) and of 28% (14/50) when E2 levels were ≥409 pg/mL (≥1,500 pg/mL). In a logistic regression analysis, adjusting for serum P4 level ≥11 ng/mL or <11 ng/mL (≥35 nmol or <35 nmol/L) on the day of transfer, body mass index, age at oocyte retrieval, day 5 or 6 vitrified blastocysts, and blastocyst score, the adjusted risk difference of live birth was -0.21 (-0.32; -0.10) when the E2 level was <292 pg/mL (<1,070 pmol/L) and -0.31 (-0.45; -0.18) when the E2 level was ≥409 pg/mL (≥1,500 pmol/L) compared with E2 levels ≥292 pg/mL and <409 pg/mL (≥1,070 and <1,500 pmol/L). Importantly, only 25% of patents had optimal levels. CONCLUSION: The study shows a significant association between serum E2 levels and reproductive outcomes in an HRT-FET cohort in which optimal serum P4 levels were secured. Midluteal serum E2 levels are associated with the LBR in HRT-FET cycles, and E2 levels should neither be too high nor too low. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT No.: 2019-001539-29.

The effectiveness of social-support-based weight-loss interventions-a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis examined the effectiveness of social-support-based weight-loss interventions in adult populations with excess weight or obesity. METHODS: We performed a systematic review of randomized controlled trials that reported on the effectiveness of weight-loss interventions which incorporated a social connectedness component. To this end, we conducted a rigorous database search of MEDLINE, Embase, PsycINFO, CINAHL, Cochrane, and PubMed for relevant articles. The quality of eligible trials was evaluated by the Cochrane Risk-of-Bias2 tool. Five meta-analyses on intervention effectiveness in terms of weight loss were executed at 2-4-month assessment, 6-month assessment, end of intervention, and 3- and 6-month follow-up. RESULTS: Twenty-four trials involving couples or peers targeting weight loss in 4 919 adults with BMI ≥ 25 met inclusion criteria. Meta-analyses detected no significant effect of social-support-based weight-loss interventions at either 2-4 month or 6-month assessment. There were, however, significant effects at end of intervention [95% CI 0.39, p = 0.04] and at 3-month [95% CI 0.63, p < 0.01] and 6-month [95% CI 0.34, p = 0.05] follow-up. CONCLUSIONS: There seem to be a significant effect at the end of intervention and 3- and 6-month follow-up. However, further high-quality studies are needed before drawing any clear conclusions. TRIAL REGISTRATION: PROSPERO 2020 CRD42020173696.

CSF hyperdynamics in rats mimicking the obesity and androgen excess characteristic of patients with idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a syndrome exhibiting elevated intracranial pressure (ICP), visual disturbances, and severe headache. IIH primarily affects young obese women, though it can occur in individuals of any age, BMI, and sex. IIH is characterized by systemic metabolic dysregulation with a profile of increased androgen hormones. However, the contribution of obesity/hormonal perturbations to cerebrospinal fluid (CSF) dynamics remains unresolved. METHODS: We employed obese female Zucker rats and adjuvant testosterone to reveal IIH causal drivers. ICP and CSF dynamics were determined with in vivo experimentation and magnetic resonance imaging, testosterone levels assessed with mass spectrometry, and choroid plexus function revealed with transcriptomics. RESULTS: Obese rats had undisturbed CSF testosterone levels and no changes in ICP or CSF dynamics. Adjuvant testosterone treatment of obese rats elevated the CSF secretion rate, although with no effect on the ICP, due to elevated CSF drainage capacity of these rats. CONCLUSIONS: Obesity in itself therefore does not suffice to recapitulate the IIH symptoms in rats, but modulation of CSF dynamics appears with adjuvant testosterone treatment, which mimics the androgen excess observed in female IIH patients. Obesity-induced androgen dysregulation may thus contribute to the disease mechanism of IIH and could potentially serve as a future therapeutic target.

Intraoperative Irrigation and Risk of Chronic Subdural Hematoma Recurrence.

BACKGROUND AND OBJECTIVES: In most neurosurgical centers, irrigation is an essential part of the surgical procedure for chronic subdural hematoma (CSDH). However, it is unknown whether the volume of irrigation fluid affects the risk of CSDH recurrence. This study aimed to investigate a potential association between the volume of irrigation fluid used during burr hole evacuation of CSDH and the risk of CSDH recurrence. METHODS: This study is a subanalysis of 2 randomized trials (Drain Time & Drain Time 2) designed to investigate the effect of drainage duration on the recurrence of CSDH. Intraoperative irrigation volume was measured, and patients were followed for 90 days for recurrent CSDH. RESULTS: A total of 525 patients with CSDH were included. There was no significant difference in the volume of irrigation fluid used between patients with recurrence (mean = 938 mL, SD = ±552) and without recurrence (mean = 852 mL, SD = ±454) ( P -value = .15). Patients with recurrent CSDH had larger primary CSDH volumes (mean = 134 cm 3 , SD = ±69) than patients without recurrence (mean = 119 cm 3 , SD = ±58) ( P = .04). Multiple logistic regression analysis revealed no association between irrigation volume and recurrence, also when stratified for hematoma size. CONCLUSION: There was no significant association between irrigation volume and recurrent CSDH within 90 days in patients undergoing burr hole surgery for CSDH.

Modelling idiopathic intracranial hypertension in rats: contributions of high fat diet and testosterone to intracranial pressure and cerebrospinal fluid production.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure (ICP), impaired vision, and headache. Most cases of IIH occur in obese women of childbearing age, though age, BMI, and female sex do not encompass all aspects of IIH pathophysiology. Systemic metabolic dysregulation has been identified in IIH with a profile of androgen excess. However, the mechanistic coupling between obesity/hormonal perturbations and cerebrospinal fluid dynamics remains unresolved. METHODS: Female Wistar rats were either fed a high fat diet (HFD) for 21 weeks or exposed to adjuvant testosterone treatment for 28 days to recapitulate IIH causal drivers. Cerebrospinal fluid (CSF) and blood testosterone levels were determined with mass spectrometry, ICP and CSF dynamics with in vivo experimentation, and the choroid plexus function revealed with transcriptomics and ex vivo isotope-based flux assays. RESULTS: HFD-fed rats presented with increased ICP (65%), which was accompanied by increased CSF outflow resistance (50%) without altered CSF secretion rate or choroid plexus gene expression. Chronic adjuvant testosterone treatment of lean rats caused elevated ICP (55%) and CSF secretion rate (85%), in association with increased activity of the choroid plexus Na+,K+,2Cl- cotransporter, NKCC1. CONCLUSIONS: HFD-induced ICP elevation in experimental rats occurred with decreased CSF drainage capacity. Adjuvant testosterone, mimicking the androgen excess observed in female IIH patients, elevated the CSF secretion rate and thus ICP. Obesity-induced androgen dysregulation may thus contribute to the disease mechanism of IIH.

The metabolome of pink-footed goose: Heavy metals and lipid metabolism.

Wildlife is exposed to mixtures of environmental contaminants that affect health and population dynamics. Exposure to toxic heavy metals originating from anthropogenic sources may exert metabolic effects at even low exposure concentrations. Here we investigated the relationships between heavy metal exposure and metabolic changes in the migratory bird pink-footed goose (Anser brachyrhynchus). We used blood pellet and blood plasma samples from 27 free-ranging pink-footed geese to study heavy metal (Cd, Cr, Hg, and Pb) exposure in relation to the metabolome. The results relate blood concentrations of Cd (range: 0.218-1.09 ng/g), Cr (range: 0.299-5.60 ng/g), and Hg (range: 2.63-6.00 ng/g) to signal areas of fatty acids and other lipids, while no correlations were identified for Pb level (range: 21.0-64.2 ng/g) exposure. Lipid signal areas were negatively associated with concentrations of Cr and positively associated with Hg exposure (both p < 0.05). α-Linolenic acid and 9-oxononanoic acid were negatively correlated to Cr exposure (both p < 0.05) and were related in the α-linolenic acid metabolism pathway. Compared to known thresholds for aviary species, the heavy metal concentrations are below levels of toxicity, which may explain the low number of metabolites that significantly change. Nevertheless, the heavy metal exposure is still correlated to changes in the lipid metabolism that may reduce migrating birds' breeding success and increase mortality for an exposed part of the population.

Human visceral and subcutaneous adipose stem and progenitor cells retain depot-specific adipogenic properties during obesity.

Abdominal obesity associates with cardiometabolic disease and an accumulation of lipids in the visceral adipose depot, whereas lipid accumulation in the subcutaneous depot is more benign. We aimed to further investigate whether the adipogenic properties where cell-intrinsic, or dependent on a depot-specific or obesity-produced microenvironment. We obtained visceral and subcutaneous biopsies from non-obese women (n = 14) or women living with morbid obesity (n = 14) and isolated adipose stem and progenitor cells (ASPCs) from the stromal vascular fraction of non-obese (n = 13) and obese (n = 13). Following in vitro differentiation into mature adipocytes, we observed a contrasting pattern with a lower gene expression of adipogenic markers and a higher gene expression of immunogenic markers in the visceral compared to the subcutaneous adipocytes. We identified the immunogenic factor BST2 as a marker for visceral ASPCs. The effect of obesity and insulin resistance on adipogenic and immunogenic markers in the in vitro differentiated cells was minor. In contrast, differentiation with exogenous Tumor necrosis factor resulted in increased immunogenic signatures, including increased expression of BST2, and decreased adipogenic signatures in cells from both depots. Our data, from 26 women, underscore the intrinsic differences between human visceral and subcutaneous adipose stem and progenitor cells, suggest that dysregulation of adipocytes in obesity mainly occurs at a post-progenitor stage, and highlight an inflammatory microenvironment as a major constraint of human adipogenesis.

Modulating Heart Rate Variability through Deep Breathing Exercises and Transcutaneous Auricular Vagus Nerve Stimulation: A Study in Healthy Participants and in Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus.

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are associated with an impaired autonomic nervous system and vagus nerve function. Electrical or physiological (deep breathing-DB) vagus nerve stimulation (VNS) could be a potential treatment approach, but no direct comparison has been made. In this study, the effect of transcutaneous auricular VNS (taVNS) and DB on vagal tone was compared in healthy participants and RA or SLE patients. The vagal tone was estimated using time-domain heart-rate variability (HRV) parameters. Forty-two healthy participants and 52 patients performed 30 min of DB and 30 min of taVNS on separate days. HRV was recorded before and immediately after each intervention. For the healthy participants, all HRV parameters increased after DB (SDNN + RMSSD: 21-46%), while one HRV parameter increased after taVNS (SDNN: 16%). For the patients, all HRV parameters increased after both DB (17-31%) and taVNS (18-25%), with no differences between the two types of VNS. DB was associated with the largest elevation of the HRV parameters in healthy participants, while both types of VNS led to elevated HRV parameters in the patients. The findings support a potential use of VNS as a new treatment approach, but the clinical effects need to be investigated in future studies.

Investigating the Dose-Response Relationship between Deep Breathing and Heart Rate Variability in Healthy Participants and Across-Days Reliability in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are associated with autonomic dysfunction, potentially through reduced vagus nerve tone. Vagus nerve stimulation has been proposed as an anti-inflammatory treatment, and it can be performed through deep breathing (DB) exercises. In this study, the dose-response relationship between DB exercises and heart rate variability (HRV) was investigated in healthy participants and reliability across days in patients with RA and SLE. On three separate days, 41 healthy participants performed DB for: 5, 15, or 30 min. On two separate days, 52 RA or SLE patients performed DB with the dose associated with the highest HRV increase in healthy participants. The HRV was estimated from ECG-recordings recorded prior and post the DB exercises. Increases in dose led to larger HRV-responses. Thirty minutes led to the largest HRV-response. In the RA and SLE patients, this dose increased the HRV-parameters consistently across the two days, indicating reliability. DB increases HRV in healthy participants and RA or SLE patients, which indicates stimulation of the vagus nerve. Of the tested durations, 30 min of DB was the optimal period of stimulation. A potential anti-inflammatory effect of DB exercises should be investigated in future studies.

Quantification of urinary albumin and -creatinine: A comparison study of two analytical methods and their impact on albumin to creatinine ratio.

OBJECTIVES: Assessment of albuminuria through albumin to creatinine ratio (ACR) is a widely used method to identify and monitor kidney damage. Significant interassay differences in urinary albumin quantification have been documented, which may affect ACR. This study was conducted to assess quantification of urinary albumin and urinary creatinine by two different analytical platforms, Cobas 6000 and Atellica CH 930, to examine the concordance of ACR stratification. METHOD: 60 urinary albumin and 60 urinary creatinine concentrations were analyzed by Cobas 6000 and Atellica CH 930 using immunoturbidimetric assays for urinary albumin quantification and enzymatic assays for urinary creatinine quantification. Analytical performance was evaluated using Passing Bablok regression, Bland Altman plots, desirable specifications for inaccuracy and imprecision, and Wilcoxon test. Clinical significance was assessed through total error allowance (TEa) and concordance of ACR categories through Cohen's Kappa coefficient. Imprecision was assessed using control material of two levels. RESULTS: Results were within desirable specifications for inaccuracy. Statistical differences were found (p < 0.05) for both analytes. TEa results were exchangeable for urinary creatinine, whereas no exchangeability was found for urinary albumin. Cohen's Kappa confirmed an almost perfect agreement of ACRs between the two methods (K = 0.87), testing 42 samples. Five of the 42 samples were stratified into different categories of ACR. Results from control material were within limits of acceptable imprecision (CV < 5%). CONCLUSIONS: The findings of the study suggest that while differences in urinary creatinine results are not clinically significant, differences in urinary albumin results are. Despite an almost perfect agreement between the ACR results from Cobas 6000 and Atellica CH 930, there is a risk of incorrectly understanding a patient's kidney disease progression.

Pilot-scale hydrolysis of primary sludge for production of easily degradable carbon to treat biological wastewater or produce biogas.

Organic compounds in wastewater are required for the biological removal of nitrogen, but they can also be used for biogas production. Distribution of the internal organic carbon at the plant is therefore critical to ensure high quality of the treated water, reduce greenhouse gas emissions, and optimize biogas production. We describe a wastewater treatment plant designed to focus equally on energy production, water quality, and reduced emissions of greenhouse gases. A disk filter was installed to remove as much carbon as possible during primary treatment. Primary sludge was then hydrolyzed and centrifuged. The hydrolysate centrate contained volatile fatty acids and was used either for the secondary wastewater treatment or to produce biogas. The yield during hydrolysis was 30-35 g volatile fatty acid per kg dry material or 40-65 g soluble COD per kg total solid. The specific denitrification rate was 20-40 g/(g·min), which is on the same order of magnitude as that for commonly used external carbon sources. Hydrolysis at around 35 °C and pH 7 gave the best results. The hydrolysate centrate can be stored and added to the biological treatment to improve water quality and reduce emissions of nitrous oxide or it can be used to produce biogas to optimize the operation of the plant.

Randomised controlled cognition trials in remitted patients with mood disorders published between 2015 and 2021: A systematic review by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Cognitive impairments are an emerging treatment target in mood disorders, but currently there are no evidence-based pro-cognitive treatments indicated for patients in remission. With this systematic review of randomised controlled trials (RCTs), the International Society for Bipolar Disorders (ISBD) Targeting Cognition Task force provides an update of the most promising treatments and methodological recommendations. METHODS: The review included RCTs of candidate pro-cognitive interventions in fully or partially remitted patients with major depressive disorder or bipolar disorder. We followed the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE and Cochrane Library from January 2015, when two prior systematic reviews were conducted, until February 2021. Two independent authors reviewed the studies with the Revised Cochrane Collaboration's Risk of Bias tool for Randomised trials. RESULTS: We identified 16 RCTs (N = 859) investigating cognitive remediation (CR; k = 6; N = 311), direct current or repetitive magnetic stimulation (k = 3; N = 127), or pharmacological interventions (k = 7; N = 421). CR showed most consistent cognitive benefits, with two trials showing improvements on primary outcomes. Neuromodulatory interventions revealed no clear efficacy. Among pharmacological interventions, modafinil and lurasidone showed early positive results. Sources of bias included small samples, lack of pre-screening for objective cognitive impairment, no primary outcome and no information on allocation sequence masking. CONCLUSIONS: Evidence for pro-cognitive treatments in mood disorders is emerging. Recommendations are to increase sample sizes, pre-screen for impairment in targeted domain(s), select one primary outcome, aid transfer to real-world functioning, investigate multimodal interventions and include neuroimaging.

[Non-pharmacological treatment of migraine and tension-type headache].

Migraine and tension-type headache are among the most frequent diseases of the world. As pharmacological treatment often is associated with distinct side effects, there is an increasing need for non-pharmacological treatment options. However, there has been a striking lack of evidence with regards to the efficacy of the huge variety of non-pharmacological interventions. In this review, we present the available evidence for the most common non-pharmacological treatment options with focus on the national clinical guideline for non-pharmacological treatment of headache disorders published in 2021.

The impact of hypoglycaemia in children and adolescents with type 1 diabetes on parental quality of life and related outcomes: A systematic review.

This systematic review aims to summarize and critically evaluate the current evidence regarding the impact of hypoglycaemia in children and adolescents with type 1 diabetes on parental quality of life. MEDLINE, PsycINFO, CINAHL, and the Cochrane Library were searched. Inclusion criteria were: 1) quantitative design, 2) included parents of children or adolescents with type 1 diabetes, 3) assessment of hypoglycemia in children/adolescents with type 1 diabetes, 4) assessment of parent quality of life (or related domains of life), and 5) analysis of the relationship(s) between the child's hypoglycaemia and parents' quality of life. The data were summarised in accordance with Synthesis Without Meta-Analysis Guidelines. Twelve studies were included, reporting data from 1895 parents across six countries. Ten studies were cross-sectional; two included prospective data. Evidence suggested that greater frequency and severity of hypoglycemia was associated with greater parental fear of hypoglycemia, emotional distress and family burden. Children's hypoglycaemia has a negative impact on the well-being of parents, but there is an absence of evidence regarding the impact on their overall quality of life. Research into the hypoglycaemia-specific quality of life of parents is needed to explore the impact on various areas, such as social and physical dimensions.

Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial.

OBJECTIVE: To investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty. DESIGN: Randomised, blinded, placebo controlled trial with follow-up at 90 days. SETTING: Five Danish hospitals, September 2018 to March 2020. PARTICIPANTS: 485 adult participants undergoing total knee arthroplasty. INTERVENTION: A computer generated randomised sequence stratified for site was used to allocate participants to one of three groups: DX1 (dexamethasone (24 mg)+placebo); DX2 (dexamethasone (24 mg)+dexamethasone (24 mg)); or placebo (placebo+placebo). The intervention was given preoperatively and after 24 hours. Participants, investigators, and outcome assessors were blinded. All participants received paracetamol, ibuprofen, and local infiltration analgesia. MAIN OUTCOME MEASURES: The primary outcome was total intravenous morphine consumption 0 to 48 hours postoperatively. Multiplicity adjusted threshold for statistical significance was P<0.017 and minimal important difference was 10 mg morphine. Secondary outcomes included postoperative pain. RESULTS: 485 participants were randomised: 161 to DX1, 162 to DX2, and 162 to placebo. Data from 472 participants (97.3%) were included in the primary outcome analysis. The median (interquartile range) morphine consumptions at 0-48 hours were: DX1 37.9 mg (20.7 to 56.7); DX2 35.0 mg (20.6 to 52.0); and placebo 43.0 mg (28.7 to 64.0). Hodges-Lehmann median differences between groups were: -2.7 mg (98.3% confidence interval -9.3 to 3.7), P=0.30 between DX1 and DX2; 7.8 mg (0.7 to 14.7), P=0.008 between DX1 and placebo; and 10.7 mg (4.0 to 17.3), P<0.001 between DX2 and placebo. Postoperative pain was reduced at 24 hours with one dose, and at 48 hours with two doses, of dexamethasone. CONCLUSION: Two doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain. TRIAL REGISTRATION: Clinicaltrials.gov NCT03506789.