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Introduction: The correlation between body mass index (BMI) and utility in participants with obesity was assessed using health-related quality-of-life data collected in two weight loss intervention studies, SCALE and STEP 1., Methods: Short Form Health Survey 36-Item (SF-36) scores from SCALE and STEP 1 were mapped to EuroQoL-5 dimensions-3 levels (EQ-5D-3L) using an established algorithm to derive utilities for the UK. SF-36 scores from STEP 1 were converted into Short Form 6 dimension (SF-6D) utilities for Portugal using the tool developed by the University of Sheffield. The correlation between baseline BMI and utility was assessed by multiple linear regression analyses, controlling for demographic and clinical parameters., Results: A higher baseline BMI correlated with lower EQ-5D-3L and SF-6D utilities, although the trend was non-significant. Assuming linearity between BMI ranges 30-40 kg/m 2 , an additional unit of BMI correlated with 0.0041 and 0.0031 lower EQ-5D-3L scores in SCALE and 0.0039 and 0.0047 lower EQ-5D-3L and 0.0027 and 0.0020 lower SF-6D scores in STEP 1 for men and women, respectively., Conclusion: In individuals with comparable demographic characteristics and weight-related comorbidities, a 1 unit change in BMI leads to a difference of up to 0.005 in utility indices., Trial Registration: ClinicalTrials.gov identifiers: SCALE (NCT01272219) and STEP 1 (NCT03548935)., (© 2024. The Author(s).)

Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1β. While transient exposure to low IL-1β concentrations improves insulin secretion and β-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective β-cell death. IL-1 is secreted locally by islet-resident macrophages and β-cells; however, it is unknown if and how the two opposing modes may emerge at single islet level. We investigated the duality of IL-1β with a quantitative in silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through the IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NF-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway-IL-1 receptor antagonist and A20, among others. A transient response ensues when the two feedbacks are balanced. When the positive feedback dominates over the negative, islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1β amplifying cells are more prone to transit into persistent IL-1β mode. Our results are likely not limited to IL-1β but are general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedback mechanisms of opposing nature and acting on different time scales provides a number of testable predictions. Taking islet architecture and cellular heterogeneity into consideration, further dynamic monitoring and experimental validation in actual islet samples will be crucial to verify the model predictions and enhance its utility in clinical applications., (© 2024. The Author(s).)

Aim: To provide an updated estimate of the association between body mass index (BMI) and health-related quality of life (HRQoL) among the general population in England and to identify population subgroups with the highest potential utility gains from obesity interventions., Materials and Methods: The sample included 12 158 adults with valid HRQoL and BMI data from the 2017 and 2018 Health Survey for England. Robust standard error linear regression, controlling for demographic and socioeconomic characteristics, lifestyle behaviours and obesity-related comorbidities, was used for the baseline analysis. Robustness checks assessed the impact of (a) estimator selection; (b) model specifications; (c) statistical outliers at high BMI; (d) potential BMI measurement error; and (e) data pooling., Results: The study found a significant association between HRQoL and BMI, which exhibited an inverted U-shaped relationship. The mean HRQoL peaked at 25.7 kg/m 2 in men and 22.6 kg/m 2 in women and was reduced in the underweight, overweight and obesity BMI ranges. Sensitivity analyses reported similar coefficients, suggesting a robust model specification., Conclusions: Reduced HRQoL beyond optimal BMI underlines the importance of maintaining a normal BMI range for overall health. The rising prevalence of class III obesity is a major public health concern given its disproportionate impact on health, health care utilization and costs. Obesity management is key to preventing the reduction in HRQoL associated with obesity-related comorbidities, and this analysis supports the development of targeted policies and population health initiatives for people with class III obesity., (© 2024 Novo Nordisk A/S. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: This study aimed to determine the comparative treatment effects of semaglutide 2.4 mg and placebo on health utility index scores [6-dimension short-form survey (SF-6D)] with Australian weights in full analysis set (FAS) and in post-hoc subgroups of the STEP 1 trial, defined according to different body mass index (BMI) cut-off points and presence of comorbidities at baseline. The study also explored the correlation between baseline BMI and SF-6D in the STEP 1 trial population., Methods: The 36-item SF survey (SF-36) scores from STEP 1 were mapped to SF-6D health states and converted to utility index scores using an Australian valuation algorithm. The change from baseline in SF-6D utility score (95% confidence intervals) was compared between semaglutide 2.4 mg and placebo at week 68 using the mixed model for repeated measurements approach. The relationship between utility scores and BMI at baseline was assessed by multiple linear regression analyses, controlling for demographic and clinical parameters., Results: The estimated mean treatment difference in SF-6D utility score favoured semaglutide 2.4 mg, and, at week 68, it was 0.057 (0.038-0.076) for the FAS. A greater treatment effect was noted in subgroups with presence of symptomatic comorbidities, i.e. 0.077 (0.027-0.128) to 0.105 (0.030-0.179) at week 68. A 1-unit increase in BMI was associated with a utility loss of 0.0075 (-0.0089 to -0.0062) for the FAS population, while controlling for demographic and clinical parameters., Conclusion: To our knowledge, this is the first study showing statistically significant and clinically meaningful improvements in SF-6D utility scores with weight-loss pharmacotherapy in Australia., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: In the Semaglutide Treatment Effect in People with obesity (STEP) trials, once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention reduced body weight and improved cardiometabolic parameters in adults with obesity (or overweight with weight-related comorbidities). Effects on the risk of developing type 2 diabetes (T2D) require investigation., Methods: STEP 1 (68 weeks) and 5 (104 weeks) randomized participants to semaglutide 2.4 mg or placebo. STEP 4 included a 20-week semaglutide run-in followed by randomization to 48 weeks of continued semaglutide or withdrawal (placebo). Ten-year T2D risk scores were calculated post hoc using Cardiometabolic Disease Staging., Results: In STEP 1 (N = 1583), relative risk score reductions were greater with semaglutide versus placebo (semaglutide: -61.1%; placebo: -12.9%; p < 0.0001). These reductions were maintained to week 104 in STEP 5 (N = 295; semaglutide: -60.0%; placebo: 3.5%; p < 0.0001). Risk scores during the STEP 4 run-in period (N = 776) were reduced from 20.6% to 11.1% and further to 7.7% at week 68 with continued semaglutide, increasing to 15.4% with withdrawal (relative risk score change: semaglutide: -32.1%; placebo: +40.6%; p < 0.0001). Risk score reductions mirrored weight loss., Conclusions: Cardiometabolic Disease Staging risk assessment suggests that once-weekly semaglutide 2.4 mg may substantially lower 10-year T2D risk in people with overweight or obesity., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Background: We assessed the efficacy and safety of the oral glucagon-like peptide-1 analogue, semaglutide 50 mg, taken once per day versus placebo for the treatment of overweight or obesity in adults without type 2 diabetes., Methods: This randomised, double-blind, placebo-controlled, phase 3, superiority trial enrolled adults with a BMI of at least 30 kg/m 2 , or at least 27 kg/m 2 with bodyweight-related complications and comorbidities, without type 2 diabetes. The trial was done at 50 outpatient clinics in nine countries across Asia, Europe, and North America. Participants were randomly allocated (1:1) via an interactive web-response system to oral semaglutide escalated to 50 mg, or visually matching placebo, once per day for 68 weeks, plus lifestyle intervention. Group assignment was masked for participants, investigators, and those assessing outcomes. Coprimary endpoints were the percentage change in bodyweight and whether participants reached a bodyweight reduction of at least 5% at week 68 for oral semaglutide 50 mg versus placebo, assessed regardless of treatment discontinuation or use of other bodyweight-lowering therapies (an intention-to-treat analysis). Safety was assessed in participants who received at least one dose of trial drug. This trial, registered with ClinicalTrials.gov (NCT05035095), is now complete., Findings: From Sept 13 to Nov 22, 2021, 709 participants were screened, of whom 667 were randomly assigned to oral semaglutide 50 mg (n=334) or placebo (n=333). The estimated mean bodyweight change from baseline to week 68 was -15·1% (SE 0·5) with oral semaglutide 50 mg versus -2·4% (0·5) with placebo (estimated treatment difference -12·7 percentage points, 95% CI -14·2 to -11·3; p<0·0001). More participants reached bodyweight reductions of at least 5% (269 [85%] of 317 vs 76 [26%] of 295; odds ratio [OR] 12·6, 95% CI 8·5 to 18·7; p<0·0001), 10% (220 [69%] vs 35 [12%]; OR 14·7, 9·6 to 22·6), 15% (170 [54%] vs 17 [6%]; OR 17·9, 10·4 to 30·7), and 20% (107 [34%] vs 8 [3%]; OR 18·5, 8·8 to 38·9) at week 68 with oral semaglutide 50 mg versus placebo. Adverse events were more frequent with oral semaglutide 50 mg (307 [92%] of 334) than with placebo (285 [86%] of 333). Gastrointestinal adverse events (mostly mild to moderate) were reported in 268 (80%) participants with oral semaglutide 50 mg and 154 (46%) with placebo., Interpretation: In adults with overweight or obesity without type 2 diabetes, oral semaglutide 50 mg once per day led to a superior and clinically meaningful decrease in bodyweight compared with placebo., Funding: Novo Nordisk., Competing Interests: Declaration of interests FKK has consulted for 89bio, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pharmacosmos, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; received research grants from Chr Hansen, Novo Nordisk, and Zealand Pharma; received honoraria for lectures, presentations, and educational events from 89bio, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pharmacosmos, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; received support for attendance at scientific meetings from Bayer, Boehringer Ingelheim, and Novo Nordisk; has participated in data safety monitoring boards or advisory boards for 89bio, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; and has received study drugs for clinical trials from Boehringer Ingelheim, Chr Hansen, Eli Lilly, Novo Nordisk, and Sanofi. FKK is a minority shareholder in Antag Therapeutics, a co-owner of the weight loss clinic Medicinsk Vægttabsbehandling ApS, and holds a patent for GIP peptide analogues (assignee University of Copenhagen; patent EP3189072B1, European Patent Office). VRA has received medical writing support from Novo Nordisk; consultancy fees from Applied Therapeutics, Fractyl, Novo Nordisk, Pfizer, and Sanofi; research grant support (to institution) from Applied Therapeutics, Eli Lilly, Fractyl, Novo Nordisk, and Sanofi; and support for attendance at investigator meetings and scientific conferences for related presentations from Eli Lilly, Fractyl, and Novo Nordisk. VRA's spouse is an employee of Janssen. RDdV and TH-H are employees of, and shareholders in, Novo Nordisk. PNL is an employee of Novo Nordisk. JR has received grants or research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Merck, Oramed, Novartis, Novo Nordisk, Pfizer, and Sanofi; has served on scientific advisory boards and received honorarium or consulting fees from Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Terns Pharma, and Zealand Pharma; and has received honoraria for lectures from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi. DMR has received medical writing support from Novo Nordisk; has been a clinical investigator for AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; has received consulting fees from Boehringer Ingelheim, Kayentis, and Novo Nordisk; has acted as an unpaid consultant for Eli Lilly; has received honoraria as a speaker from Boehringer Ingelheim and Novo Nordisk; has received personal fees from the American Diabetes Association, the Endocrine Society, Medscape, PeerView, and Prime Therapeutics for the development of continuing medical education materials; has received support for attendance at scientific congresses by the American Diabetes Association, the Endocrine Society, Medscape, Novo Nordisk, PeerView, and Prime Therapeutics; has participated in scientific advisory boards for Boehringer Ingelheim and Novo Nordisk; and is a shareholder in Eli Lilly. WTG has received medical writing support from Novo Nordisk; has served as a site principal investigator for multicentred clinical trials sponsored by his university and funded by Eli Lilly, Epitomee, Neurovalens, Novo Nordisk, and Pfizer; has served as a consultant on advisory boards for Alnylam Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Fractyl Health, Inogen, Merck, Novo Nordisk, and Pfizer; and has served on the executive committee of the American Association of Clinical Endocrinology (term expired May, 2021)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aim: To assess health utility values in the Semaglutide Treatment Effect in People with obesity (STEP) 1-4 trials., Materials and Methods: The STEP 1-4 phase 3a, 68-week, double-blind randomized controlled trials assessed the efficacy and safety of semaglutide 2.4 mg versus placebo in individuals with a body mass index (BMI) of 30 kg/m 2 or higher or a BMI of 27 kg/m 2 or higher and at least one comorbidity (STEP 1, 3 and 4), or a BMI of 27 kg/m 2 or higher and type 2 diabetes (STEP 2). Patients received lifestyle intervention plus intensive behavioural therapy in STEP 3. Health-related quality of life was assessed using the Short Form 36-item Health Survey version 2 (SF-36v2) at baseline and week 68. Scores were converted into Short Form Six-Dimension version 2 (SF-6Dv2) utility scores or mapped onto the European Quality of Life Five-Dimension Three-Level (EQ-5D-3L) utility index using UK health utility weights., Results: At week 68, semaglutide 2.4 mg was associated with minor health utility score improvements from baseline (all trials), while scores for placebo typically decreased. SF-6Dv2 treatment differences by week 68 for semaglutide 2.4 mg versus placebo were significant in STEP 1 and 4 (P ≤ .001), but not STEP 2 or 3. EQ-5D-3L treatment differences by week 68 for semaglutide 2.4 mg versus placebo were significant in STEP 1, 2 and 4 (P < .001 for all), but not STEP 3., Conclusions: Semaglutide 2.4 mg was associated with improvement in health utility scores compared with placebo, reaching statistical significance in STEP 1, 2 and 4., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Infected cells communicate through secreted signaling molecules like cytokines, which carry information about pathogens. How differences in cytokine secretion affect inflammatory signaling over space and how responding cells decode information from propagating cytokines are not understood. By computationally and experimentally studying NF-κB dynamics in cocultures of signal-sending cells (macrophages) and signal-receiving cells (fibroblasts), we find that cytokine signals are transmitted by wave-like propagation of NF-κB activity and create well-defined activation zones in responding cells. NF-κB dynamics in responding cells can simultaneously encode information about cytokine dose, duration, and distance to the cytokine source. Spatially resolved transcriptional analysis reveals that responding cells transmit local cytokine information to distance-specific proinflammatory gene expression patterns, creating "gene expression zones." Despite single-cell variability, the size and duration of the signaling zone are tightly controlled by the macrophage secretion profile. Our results highlight how macrophages tune cytokine secretion to control signal transmission distance and how inflammatory signaling interprets these signals in space and time.

Allele number, or zygosity, is a clear determinant of gene expression in diploid cells. However, the relationship between the number of copies of a gene and its expression can be hard to anticipate, especially when the gene in question is embedded in a regulatory circuit that contains feedback. Here, we study this question making use of the natural genetic variability of human populations, which allows us to compare the expression profiles of a receptor protein in natural killer cells among donors infected with human cytomegalovirus with one or two copies of the allele. Crucially, the distribution of gene expression in many of the donors is bimodal, which indicates the presence of a positive feedback loop somewhere in the regulatory environment of the gene. Three separate gene-circuit models differing in the location of the positive feedback loop with respect to the gene can all reproduce the homozygous data. However, when the resulting fitted models are applied to the hemizygous donors, one model (the one with the positive feedback located at the level of gene transcription) is superior in describing the experimentally observed gene-expression profile. In that way, our work shows that zygosity can help us relate the structure and function of gene regulatory networks., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)