[15O]H2O myocardial perfusion positron emission tomography: Added value of relative stress perfusion deficit in the prediction of significant coronary artery stenosis in a mixedpopulation.

BACKGROUND: It remains unknown whether estimation of the relative stress perfusion deficit offers added value in the prediction of significant coronary artery stenosis in myocardial perfusion imaging with [15O]H2O positron emission tomography (PET) in a population with high prevalence of established cardiac disease. METHODS: During eight months, we consecutively included all patients undergoing [15O]H2O PET and subsequent invasive coronary angiography (ICA). Significant stenosis was defined from ICA as fractional flow reserve ≤.8 or coronary artery narrowing of ≥70%. We calculated absolute and relative total perfusion deficits (aTPD and rTPD, respectively) as semiquantitative measures of the extent and severity of reduced stress perfusion. A multivariate logistic regression analysis was performed to test the adjusted associations (odds ratio (OR) with 95% CI) with significant coronary artery stenosis. RESULTS: Of 800 patients undergoing [15O]H2O PET, 144 underwent ICA, where 142 patients had aTPD of ≥3% and 79 (55%) of these had at least one significant stenosis. In an adjusted analysis, rTPD (OR10% increase = 2.12 (1.44-3.12), P < .001), previous coronary artery bypass grafting (CABG) (OR = .11 (.03-.36), P < .001) and reduced left ventricular ejection fraction (LVEF) (OR = .25 (.08-.84), P = .02) were independently associated with significant stenosis, whereas the association with aTPD (OR10% increase = 1.14 (.98-1.32), P = .08) was modest. CONCLUSIONS: In the presence of an absolute perfusion deficit (aTPD of ≥3%), rTPD may improve the prediction of significant stenosis in a heterogeneous population of patients examined with [15O]H2O PET. Furthermore, previous CABG and reduced LVEF are associated with nonstenotic perfusion deficiencies, suggesting caution when interpreting myocardial perfusion imaging in such patients.

82Rb and [15O]H2O myocardial perfusion PET imaging: a prospective head to head comparison.

BACKGROUND: 82Rb PET and [15O]H2O PET are both validated tracers for myocardical perfusion imaging but have not previously been compared clinically. During our site's transition from 82Rb to [15O]H2O PET, we performed a head-to-head comparison in a mixed population with suspected ischemic heart disease. METHODS: A total of 37 patients referred for perfusion imaging due to suspicion of coronary stenosis were examined with both 82Rb and [15O]H2O PET on the same day in rest and during adenosine-induced stress. The exams were rated by two blinded readers as normal, regional ischemia, globally reduced myocardial perfusion, or myocardial scarring. For [15O]H2O PET, regional ischemia was defined as two neighboring segments with average stress perfusion ≤ 2.3 mL/(min·g). Further, we evaluated a total perfusion deficit (TPD) of ≥ 10% as a more conservative marker of ischemia. RESULTS: [15O]H2O PET identified more patients with regional ischemia: 17(46%) vs 9(24%), agreement: 59% corresponding to a Cohen's kappa of .31 [95%CI .08-.53], (P < .001). Using the more conservative TPD ≥ 10%, the agreement increased to 86% corresponding to a kappa of .62 [95%CI .33-.92], (P = .001). For the subgroup of patients with no known heart disease (n = 18), the agreement was 94%. Interrater agreement was 95% corresponding to a kappa of .89 [95%CI .74-1.00] (P < .001). CONCLUSIONS: In clinical transition from 82Rb to [15O]H2O PET, it is important to take into account the higher frequency of patients with regional ischemia detected by [15O]H2O PET.

Height and bone mineral content after inhaled corticosteroid use in the first 6 years of life.

BACKGROUND: Infants and young children might be particularly susceptible to the potential side effects from inhaled corticosteroid (ICS) on height and bone mineral content (BMC), but this has rarely been studied in long-term prospective studies. METHODS: Children from two Copenhagen Prospective Studies on Asthma in Childhood cohorts were included. ICS use was registered prospectively from birth to age 6 and the cumulative dose was calculated. Primary outcomes were height and BMC from dual-energy X-ray absorptiometry (DXA) scans at age 6. RESULTS: At age 6, a total of 930 children (84%) from the cohorts had a valid height measurement and 792 (71%) had a DXA scan. 291 children (31%) received a cumulated ICS dose equivalent to or above 10 weeks of standard treatment before age 6. We found an inverse association between ICS use and height, -0.26 cm (95% CI: -0.45 to -0.07) per 1 year standard treatment from 0 to 6 years of age, p=0.006. This effect was mainly driven by children with ongoing treatment between age 5 and 6 years (-0.31 cm (95% CI: -0.52 to -0.1), p=0.004), while there was no significant association in children who stopped treatment at least 1 year before age 6 (-0.09 cm (95% CI: -0.46 to 0.28), p=0.64). There was no association between ICS use and BMC at age 6. CONCLUSIONS: ICS use in early childhood was associated with reduced height at age 6 years but only in children with continued treatment in the sixth year of life.

Preoperative imaging in primary hyperparathyroidism: Are 11 C-Choline PET/CT and 99m Tc-MIBI/123 Iodide subtraction SPECT/CT interchangeable or do they supplement each other?

OBJECTIVE: Preoperative location of hyperfunctioning parathyroid glands (HPGs) is vital when planning minimally invasive surgery in patients with primary hyperparathyroidism (PHPT). Dual-isotope subtraction scintigraphy with 99m Tc-MIBI/123 Iodide using SPECT/CT and planar pinhole imaging (Di-SPECT) has shown high sensitivity, but is challenged by high radiation dose, time consumption and cost. 11 C-Choline PET/CT (faster with a lower radiation dose) is non-inferior to Di-SPECT. We aim to clarify to what extent the two are interchangeable and how often there are discrepancies. DESIGN: This is a prospective, GCP-controlled cohort study. PATIENTS AND MEASUREMENTS: One hundred patients diagnosed with PHPT were included and underwent both imaging modalities before parathyroidectomy. Clinical implications of differences between imaging findings and negative imaging results were assessed. Surgical findings confirmed by biochemistry and pathology served as reference standard. RESULTS: Among the 90 patients cured by parathyroidectomy, sensitivity was 82% (95% confidence interval [CI]: 74%-88%) and 87% (95% CI: 79%-92%) for Choline PET and Di-SPECT, respectively, p = .88. In seven cases at least one imaging modality found no HPG. Of these, neither modality found any true HPGs and only two were cured by surgery. When a positive finding in one modality was incorrect, the alternative modality was correct in approximately half of the cases. CONCLUSION: Choline PET and Di-SPECT performed equally well and are both appropriate as first-line imaging modalities for preoperative imaging of PHPT. When the first-line modality fails to locate an HPG, additional preoperative imaging with the alternate modality offers no benefit. However, if parathyroidectomy is unsuccessful, additional imaging with the alternate modality has merit before repeat surgery.

Associations between Inhaled Corticosteroid Use in the First 6 Years of Life and Obesity-related Traits.

Rationale: Infants and young children might be particularly likely to experience the potential clinical side effects of inhaled corticosteroids (ICSs) on body mass index (BMI), adiposity rebound (AR), and body composition, but this has rarely been studied in long-term studies in this age group. Objectives: To determine the association between ICS exposure in the first 6 years of life and the BMI, AR, body composition, and blood lipid concentrations. Methods: Children from the two mother-child cohorts of the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) were included. ICS use was registered prospectively to age 6 years, and the cumulative dose was calculated. Multiple linear regression models were used for analysis. Measurements and Main Results: A total of 932 (84%) of the 1,111 children from the COPSAC cohorts had BMI data, 786 (71%) had dual-energy X-ray absorptiometry scan data at the age of 6 years, and 815 (73%) had an AR age calculated. Two hundred ninety-one children (31%) received a cumulative ICS dose higher than that from 10 weeks of standard treatment before the age of 6. ICS treatment during 0-6 years of age was associated with an increased BMI z-score (0.05 [95% confidence interval, 0.005 to 0.09] SDs per each year of standard treatment; P = 0.03) an earlier age at AR (-0.18 [95% confidence interval, -0.28 to -0.08] yr; P = 0.0006), and a 2% increased geometric mean android fat percentage (P = 0.05). ICS exposure and dual-energy X-ray absorptiometry scan data were not associated. Conclusions: ICS use in early childhood was associated with an increased BMI z-score at age 6, an earlier AR, and a trend of association with an increased android body fat percentage.

Neutrophil Pathways of Inflammation Characterize the Blood Transcriptomic Signature of Patients with Psoriasis and Cardiovascular Disease.

BACKGROUND: Patients with psoriasis have an increased risk of atherosclerotic cardiovascular disease (CVD). The molecular mechanisms behind this connection are not fully understood, but the involvement of neutrophils have drawn attention as a shared inflammatory factor. METHODS: RNA sequencing using the Illumina platform was performed on blood from 38 patients with moderate to severe psoriasis; approximately half had prior CVD. The neutrophil to lymphocyte ratio (NLR) was obtained from blood samples. Subclinical atherosclerosis was assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography and ultrasound imaging. Transcriptomic analysis for differential expression and functional enrichment were performed, followed by correlation analyses of differentially expressed genes (DEGs), NLR and subclinical measurers of CVD. RESULTS: 291 genes were differentially expressed between patients with psoriasis with and without CVD. These included 208 upregulated and 83 downregulated DEGs. Neutrophil degranulation was identified as the most significant process related to the upregulated DEGs. Genes for the neutrophil-associated markers MPO, MMP9, LCN2, CEACAM1, CEACAM6 and CEACAM8 were identified as being of special interest and their mRNA levels correlated with NLR, high-sensitive C-reactive protein and markers of subclinical CVD. CONCLUSIONS: Patients with psoriasis and CVD had an increased expression of genes related to neutrophil degranulation in their blood transcriptome compared with patients with psoriasis without CVD. NLR may be a potential biomarker of subclinical CVD in psoriasis.

Lobar Quantification by Ventilation/Perfusion SPECT/CT in Patients with Severe Emphysema Undergoing Lung Volume Reduction with Endobronchial Valves.

BACKGROUND: Endoscopic lung volume reduction (ELVR) therapy using one-way valves is used to treat chronic obstructive pulmonary disease patients with severe heterogeneous emphysema. A successful treatment results in atelectasis of the treated pulmonary lobe with subsequent reduction of ventilation (V) and perfusion (Q). OBJECTIVE: We evaluated the effects of ELVR on the targeted lobe using a new 3-dimensional ventilation and perfusion (V/Q) single-photon emission computed tomography (SPECT)/computed tomography (CT) analysis, which allows for simultaneous semi-automatic lobar pulmonary quantification of volume, ventilation and perfusion, on the first consecutive patients treated with ELVR at Rigshospitalet, Denmark. V/Q planar scintigraphy and V/Q SPECT/CT and lung function measurements were performed before and 6 months after intervention. RESULTS: We included 24 subjects (60 years, range 46-74 years; 37.5% men) with a baseline FEV1 of 25% predicted and RV of 257% predicted. V/Q SPECT/CT-assessed volume of the targeted lobe decreased by a mean of -395 mL and a relative mean of -26.8%, whilst ventilation and perfusion decreased by a relative mean of -37.1 and -25.7%. There was a significant increase in the same parameters of the non-targeted lobe(s) on the ipsilateral side. None of these changes were found in the analysis of planar V/Q imaging. The total lung volume decreased on average by -420 mL. Six months after ELVR, FEV1 had increased by 22%. Significant correlations were found between changes in FEV1 and changes in the volume of the treated lobe (SPECT/CT). CONCLUSION: Semi-automatic SPECT/CT analysis can quantify volume, ventilation and perfusion changes in pulmonary lobes and may be used in the assessment of patient eligibility for ELVR, identifying target lobes, and evaluation of the regional effects of treatment.

The impact of EndoBarrier gastrointestinal liner in obese patients with normal glucose tolerance and in patients with type 2 diabetes.

AIMS: The duodenal-jejunal bypass sleeve ((DJBS) or EndoBarrier Gastrointestinal Liner) induces weight loss in obese subjects and may improve glucose homeostasis in patients with type 2 diabetes (T2D). To explore the underlying mechanisms, we evaluated postprandial physiology including glucose metabolism, gut hormone secretion, gallbladder emptying, appetite and food intake in patients undergoing DJBS treatment. MATERIAL AND METHODS: A total of 10 normal glucose-tolerant (NGT) obese subjects and 9 age-, body weight- and body mass index-matched metformin-treated T2D patients underwent a liquid mixed meal test and a subsequent ad libitum meal test before implantation with DJBS and 1 week (1w) and 26 weeks (26w) after implantation. RESULTS: At 26w, both groups had achieved a weight loss of 6 to 7 kg. Postprandial glucagon-like peptide-1 (GLP-1) and peptide YY responses increased at 1w and 26w, but only in T2D subjects. In contrast, glucose-dependent insulinotropic polypeptide responses were reduced only by DJBS in the NGT group. Postprandial glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin responses were unaffected by DJBS in both groups. Satiety and fullness sensations were stronger and food intake was reduced at 1w in NGT subjects; no changes in appetite measures or food intake were observed in the T2D group. No effect of DJBS on postprandial gallbladder emptying was observed, and gastric emptying was not delayed. CONCLUSIONS: DJBS-induced weight loss was associated with only marginal changes in postprandial physiology, which may explain the absence of effect on postprandial glucose metabolism.

Differential microRNA expression in blood in multiple sclerosis.

BACKGROUND: microRNAs (miRNAs) regulate the expression of the genome at the post-transcriptional level. They play a role in autoimmunity and inflammation, and show potential for use as therapeutic targets in many diseases. With the recent detection of miRNAs in body fluids, the possibility for using miRNAs as diagnostic biomarkers has emerged. OBJECTIVE: We assessed whether miRNAs contribute to the altered immune activation state in relapsing-remitting multiple sclerosis (RRMS) patients and investigated the possible use of miRNAs as diagnostic biomarkers in multiple sclerosis (MS). METHODS: We performed global miRNA expression profiling analysis in peripheral blood mononuclear cells (PBMCs) and selected miRNAs were measured in plasma. We detected expression of miRNAs by real-time qPCR and compared results with cytokines related to inflammation and disease activity. Selected miRNAs were analyzed in PBMC subpopulations, after isolating them by magnetic bead separation. RESULTS: We found that among validated miRNAs, let-7d correlated with the pro-inflammatory cytokine interleukin-1B. The miR-145 was 3-fold up-regulated in MS patients; its possible use as a diagnostic biomarker in PBMCs, plasma and serum was confirmed by ROC-curve analysis (Area under the curve (AUC) 0.785, p = 0.0004; 0.785, p = 0.004; 0.981, P < 0.0001, respectively). CONCLUSIONS: RRMS patients in remission had altered expression of miRNAs. We validated miR-145 as a potential diagnostic biomarker for the diagnosis of MS in blood, plasma and serum.

Diagnostic Value of Composite and Simplified FDG-PET/CT Scores in Polymyalgia Rheumatica and the Influence of Recent Glucocorticoid Treatment-A Retrospective Diagnostic Cohort Study.

[18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) is increasingly used to demonstrate inflammation in specific sites typical for polymyalgia rheumatica (PMR). Scoring systems based on FDG uptake have been proposed to increase diagnostic accuracy. METHODS: Retrospective inclusion of 198 consecutive patients ≥40 years of age referred for FDG-PET from the Department of Rheumatology. We assessed the degree of FDG uptake in predilection sites visually, as well as semiquantitatively, and through logistic regression analyses, we evaluated the performance of existing scoring systems as well as a new, simplified scoring system, against the final clinical diagnosis at 6 months after the FDG-PET scan. RESULTS: We found high diagnostic accuracy for the diagnosis of PMR (range 0.74-0.91) using most of the existing scoring systems in glucocorticoid-naïve patients. A simplified scoring system including only periarticular FDG uptake in the shoulders and the ischiogluteal bursae retained high sensitivity and specificity (0.92 and 0.86, respectively). We found a detrimental effect on diagnostic accuracy in all scoring systems in patients treated with glucocorticoids within 4 weeks prior to FDG-PET. CONCLUSION: Most FDG-PET scoring systems perform well for the diagnosis of PMR, and there is no loss of either sensitivity or specificity in the simplest scoring systems evaluating FDG uptake in only a few selected anatomical regions. However, systemic glucocorticoid treatment up to 4 weeks prior to FDG-PET has a markedly detrimental effect on the diagnostic accuracy of all scoring systems.

Effects of levothyroxine substitution therapy on hunger and food intake in individuals with hypothyroidism.

Context: In individuals with hypothyroidism and overweight, levothyroxine substitution therapy is often expected to cause weight loss due to its effect on resting energy expenditure. However, despite levothyroxine-induced enhancement of resting energy expenditure, fat mass loss is rarely seen after levothyroxine substitution therapy. The mechanism behind this conundrum is unknown. Aim: The aim of the study was to assess the effect of levothyroxine therapy on hunger sensations and ad libitum food intake in individuals with hypothyroidism. Design and setting: Prospective cohort study of 18 newly diagnosed hypothyroid women (thyroid-stimulating hormone (TSH) >10 mU/L). Participants were investigated at diagnosis, after normalization of TSH (<4.0 mU/L), and after 6 months of successful treatment. Eighteen age and body mass index-matched healthy controls were also included. Intervention: Hypothyroid individuals were treated with levothyroxine according to European Thyroid Association guidelines. Main outcomes: Changes in hunger sensation were assessed using visual analog scales (cm) before and during a standardized mixed meal test, and food intake was measured during a subsequent ad libitum meal (g). Results: After 6 months of levothyroxine therapy, mean resting energy expenditure was increased by 144 kcal/day (10%) (P < 0.001). Weight loss was comprised of 0.8 kg fat-free mass while fat mass remained unchanged. Fasting hunger sensation increased from a mean of 4.5 (s.d. 2.2) cm to 5.5 (s.d. 2.2) cm (P = 0.047). The numerical increase in ad libitum meal intake did not reach statistical significance. Conclusion: Our data suggest that levothyroxine-induced hunger may be a culprit in the lack of fat mass loss from levothyroxine therapy.

Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis.

BACKGROUND: Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce. METHODS: We studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND). RESULTS: RRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression. CONCLUSIONS: Using a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.

Changes in quality of life 6 months after parathyroidectomy for primary hyperparathyroidism.

Objective: The extent of symptoms due to primary hyperparathyroidism (PHPT) depends on the population being studied. PHPT is mainly discovered incidentally through routine laboratory findings. Less is known about patient-experienced improvement following successful parathyroidectomy. The aim of our study was to assess the changes in the quality of life (QoL) after successful surgery using an SF-36 questionnaire. Design: This is a prospective cohort study based on questionnaires. Methods: Forty consecutive patients diagnosed with PHPT were prospectively administered an SF-36 questionnaire before and 6 months after successful parathyroidectomy. A subgroup of 18 patients answered the questionnaire at 1 and 3 months after surgery. Successful surgery was based on biochemistry and pathology reports as confirmed by an endocrinologist. Results of each SF-36 subcategory were compared to the results at baseline in order to detect changes in patient-reported QoL after successful surgery. Results: There were significant improvements in six of eight SF-36 subcategories: vitality (P = 0.0001), physical functioning (P = 0.04), general health perception (P = 0.004), physical role functioning (P = 0.04), social role functioning (P = 0.004), and mental health perception (P = 0.0001). Changes appeared within a month after surgery with no further significant changes at later time points. Conclusions: Parathyroidectomy significantly improves QoL as measured by a decrease in SF-36 scores as early as 1 month after successful parathyroidectomy. The SF-36 QoL questionnaire is suitable for monitoring changes in patient well-being after successful parathyroidectomy.

High-dose vitamin D supplementation in pregnancy and 25(OH)D sufficiency in childhood reduce the risk of fractures and improve bone mineralization in childhood: Follow-up of a randomized clinical trial.

BACKGROUND: Exposure to vitamin D in early life has been associated with improved bone mineralization, but no studies have investigated the combined effect of pregnancy supplementation and childhood 25(OH)D concentrations on bone health. METHODS: We analyzed the effect of serum 25(OH)D concentrations at age 6 months and 6 years and the combined effect with prenatal high-dose vitamin D (2800 vs. 400 IU/day) on bone mineral density (BMD) and content (BMC) assessed by dual-energy X-ray absorptiometry (DXA) scans at age 3 and 6 years and longitudinal risk of fractures in a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) mother-child cohort with enrollment from March 4, 2009, to November 17, 2010, and clinical follow-up until January 31, 2019 (NCT00856947). All participants randomized to intervention and with complete data were included in the analyses. FINDINGS: At age 6 months, serum 25(OH)D concentration was measured in 93% (n = 541) of 584 children. Children with sufficient (≥ 75 nmol/l) vs. insufficient (< 75 nmol/l) concentrations did not have lower risk of fractures: incidence rate ratio (95% CI); 0.64 (0.37;1.11), p = 0.11. However, vitamin D sufficient children from mothers receiving high-dose supplementation during pregnancy had a 60% reduced incidence of fractures compared with vitamin D insufficient children from mothers receiving standard-dose: 0.40 (0.19;0.84), p = 0.02.At age 6 years, serum 25(OH)D concentration was measured in 83% (n = 318) of 383 children with available DXA data. Whole-body bone mineralization was higher in vitamin D sufficient children at age 6 years; BMD, adjusted mean difference (aMD) (95% CI): 0.011 g/cm2 (0.001;0.021), p = 0.03, and BMC, aMD: 12.3 g (-0.8;25.4), p = 0.07, with the largest effect in vitamin D sufficient children from mothers receiving high-dose vitamin D supplementation; BMD, aMD: 0.016 g/cm2 (0.002;0.030), p = 0.03, and BMC, aMD: 23.5 g (5.5;41.5), p = 0.01. INTERPRETATION: Childhood vitamin D sufficiency improved bone mineralization and in combination with prenatal high-dose vitamin D supplementation reduced the risk of fractures. FUNDING: The study was supported by The Lundbeck Foundation R16-A1694, The Danish Ministry of Health 903,516, The Danish Council for Strategic Research 0603-00280B and The European Research Council 946,228.

Safety and efficacy of liraglutide versus colesevelam for the treatment of bile acid diarrhoea: a randomised, double-blind, active-comparator, non-inferiority clinical trial.

BACKGROUND: Bile acid diarrhoea is an underdiagnosed disease estimated to affect 1-2% of the general population. Case reports indicate that the glucagon-like peptide 1 receptor agonist liraglutide might be an effective treatment for bile acid diarrhoea. We aimed to investigate the safety and efficacy of liraglutide for the treatment of bile acid diarrhoea. METHODS: We conducted a randomised, double-blind, active-comparator, double-dummy, non-inferiority clinical trial at the Center for Clinical Metabolic Research at Copenhagen University Hospital-Herlev and Gentofte, Hellerup, Denmark. Patients aged 18-75 years with 75selenium-homotaurocholic acid test (SeHCAT)-verified moderate-to-severe primary bile acid diarrhoea were randomly assigned (1:1) to receive liraglutide (one daily subcutaneous injection uptitrated from 0·6-1·8 mg per day over 3 weeks) or colesevelam (three capsules of 625 mg twice daily), the standard of care, for 6 weeks following one run-in week with no treatment. The primary endpoint was the proportion of participants experiencing a reduction in daily stool frequency of 25% or greater after 6 weeks. Data from all participants were included in the analysis of the primary outcome. The non-inferiority limit was set to 15% in favour of colesevelam. This trial is registered with EudraCT (2018-003575-34) and is completed. FINDINGS: Between April 1, 2019, and Jan 31, 2021, 52 patients were enrolled; 26 were assigned to liraglutide and 26 to colesevelam. 20 (77%) of 26 participants on liraglutide and 13 (50%) of 26 on colesevelam experienced a 25% or greater reduction in stool frequency, corresponding to a significant risk difference of -27% in favour of liraglutide (one-sided 95% CI -100 to -6). Liraglutide was therefore superior to colesevelam in reducing daily stool frequency. Mild nausea with a duration of 10-21 days was reported by six participants in the liraglutide group and by one participant in the colesevelam group. No other adverse events were reported. INTERPRETATION: The superiority of liraglutide compared with colesevelam in reducing stool frequency suggests consideration of liraglutide as a potential new treatment modality for bile acid diarrhoea, although larger confirmatory trials powered for superiority are warranted. FUNDING: Novo Nordisk, Novo Nordisk Foundation, Foundation for the Advancement of Medical Science under The A.P. Møller and Chastine Mc-Kinney Møller Foundation.

Interferon-beta increases systemic BAFF levels in multiple sclerosis without increasing autoantibody production.

BACKGROUND: Treatment with interferon-beta (IFN-beta) increases B-cell activating factor of the TNF family (BAFF) expression in multiple sclerosis (MS), raising the concern that treatment of MS patients with IFN-beta may activate autoimmune B cells and stimulate the production of MS-associated autoantibodies. OBJECTIVE: To investigate whether BAFF levels are associated with disease severity/activity in untreated MS patients, and to assess the effect of IFN-beta therapy on circulating BAFF and anti-myelin basic protein (MBP) autoantibody levels. RESULTS: Twenty-three patients with relapsing-remitting MS (RRMS) were followed longitudinally from initiation of IFN-beta therapy. Their blood levels of BAFF correlated positively at baseline with the expanded disability status scale (p<0.009) and MS severity score (p<0.05), but not with disease activity as determined by the number of gadolinium-enhanced lesions. The patients were followed for up to 26 months, during which the BAFF levels remained elevated without association to increased disease activity. IFN-beta therapy caused an increase in plasma BAFF levels after both 3 and 6 months of therapy (p<0.002). However, an 11% decrease in IgM and a 33% decrease in IgG anti-MBP autoantibodies (p<0.09 and p<0.009, respectively) was observed after 6 months. CONCLUSION: Pre-treatment BAFF levels correlate with high disability scores in MS, suggesting that high BAFF expression is a negative prognostic marker. Despite its known beneficial effects, IFN-beta therapy causes a sustained increase in plasma BAFF levels, which does not translate into increased levels of anti-MBP autoantibodies.

Predictors of Improvement in Quality of Life When Treating Hypothyroidism.

BACKGROUND: Primary hypothyroidism is characterized by reduced quality of life (QoL). Although thyrotropin (TSH) is utilized as the primary indicator of thyroid disease and treatment adequacy, no simple correlation between QoL and TSH has been shown. This study aimed to investigate changes in clinically relevant predictors during initiation of levothyroxine (L-T4) therapy and their ability to predict improvement in QoL. METHOD: Quality of life was measured in patients with newly diagnosed hypothyroidism, during the initial 12 months of L-T4 therapy, by the thyroid-related patient-reported outcome questionnaire, ThyPRO-39. The main outcome measures were the Composite QoL scale and the Tiredness and Emotional Susceptibility subscales (0-100, higher scores worse). Clinical variables (resting energy expenditure (REE), body composition, thyroid function, L-T4 dose, and cognitive function tests) were evaluated as predictors of improvement in QoL by univariate and multiple regression analysis. RESULTS: Thirty-seven hypothyroid patients with a baseline median TSH of 30 mU/l and a median QoL score of 29 were included. After twelve months of L-T4 treatment, the ThyPRO-39 QoL score had significantly improved to a median score of 14, while REE per kg fat-free mass (FFM) increased significantly from a mean of 26.5 to 28.7 kcal/day/kg (p < 0.001). Change in ThyPRO-39 was not associated with a change in REE/FFM (unstandardized coefficient (USC): 0.09 with confidence interval (CI): -1.93 to 2.11, p=0.93) but was positively predicted by baseline body mass index (BMI) (USC: 1.54 with CI: 0.59 to 2.49, (p=0.002), without association with weight loss (USC: 0.33 with CI: -1.21 to 1.27, p=0.96). CONCLUSION: Improvement in QoL as measured by ThyPRO-39 after initiation of L-T4 therapy for hypothyroidism was not associated with changes in REE. High baseline BMI, but not weight loss during therapy, was associated with improvement in QoL. This trail is registered with www.Clinicaltrials.gov (registration no. https://clinicaltrials.gov/ct2/show/NCT02891668).

Biomarkers of subclinical atherosclerosis in patients with psoriasis.

Psoriasis is linked with increased risk of cardiovascular disease (CVD) that is underestimated by traditional risk stratification. We conducted a large-scale plasma proteomic analysis by use of a proximity extension assay in 85 patients with a history of moderate-to-severe psoriasis with or without established atherosclerotic CVD. Differentially expressed proteins associated with CVD were correlated with subclinical atherosclerotic markers including vascular inflammation determined by 18F-fluorodeoxyglucose positron emission tomography/computed tomography, carotid intima-media thickness (CIMT), carotid artery plaques, and coronary artery calcium score (CCS) in the patients without CVD and statin treatment. We also examined the association between the neutrophil-to-lymphocyte ratio (NLR) and subclinical atherosclerosis. In unadjusted analyses, growth differentiation factor-15 (GDF-15) levels and NLR were increased, while tumor necrosis factor (TNF)-related activation-inducing ligand (TRANCE) and TNF-related apoptosis-induced ligand (TRAIL) levels were decreased in patients with established CVD compared to those without CVD. Among patients with psoriasis without CVD and statin treatment, GDF-15 levels were negatively associated with vascular inflammation in the ascending aorta and entire aorta, and positively associated with CIMT and CCS. NLR was positively associated with vascular inflammation in the carotid arteries. Our data suggest that circulating GDF-15 levels and NLR might serve as biomarkers of subclinical atherosclerosis in patients with psoriasis.