Survodutide for treatment of obesity: rationale and design of two randomized phase 3 clinical trials (SYNCHRONIZE™-1 and -2).

Objective: The objective of this study was to describe the rationale and design of two multinational phase 3 clinical trials of survodutide, an investigational glucagon and glucagon-like peptide-1 receptor dual agonist for the treatment of obesity with or without type 2 diabetes (T2D; SYNCHRONIZE-1 and -2).

Methods: In these ongoing double-blind trials, participants were randomized to once-weekly subcutaneous injections of survodutide or placebo added to lifestyle modification. Survodutide doses are uptitrated to 3.

Survodutide for the Treatment of Obesity: Rationale and Design of the SYNCHRONIZE Cardiovascular Outcomes Trial.

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors may be more effective than GLP-1 receptor agonism alone in reducing body weight, but the cardiovascular (CV) effects are unknown. The authors describe the rationale and design of SYNCHRONIZE-CVOT, a phase 3, randomized, double-blind, parallel-group, event-driven, CV safety study of survodutide, a dual glucagon and GLP-1 receptor agonist, administered subcutaneously once weekly compared with placebo in adults with a body mass index ≥27 kg/m and established CV disease or chronic kidney disease, and/or at least 2 weight-related complications or risk factors for CV disease. The primary endpoint of SYNCHRONIZE-CVOT is time to first occurrence of the composite adjudicated endpoint of 5-point major adverse CV events.

Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study).

Background And Purpose: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study.

Materials And Methods: This retrospective cohort study was conducted at 12 European centers.

Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective.

The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs)-initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators-is dependent on the optimisation of restricted trial participant resources across multiple development programmes, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease.

Imaging Follow-Up of Nonsurgical Therapies for Lung Cancer: Expert Panel Narrative Review.

Lung cancer continues to be the most common cause of cancer-related death worldwide. In the past decade, with the implementation of lung cancer screening programs and advances in surgical and nonsurgical therapies, the survival of patients with lung cancer has increased, as has the number of imaging studies that these patients undergo. However, most patients with lung cancer do not undergo surgical re-section, because they have comorbid disease or lung cancer in an advanced stage at diagnosis.

Position paper: Models of post-transplant care for individuals with cystic fibrosis.

There is no consensus on the best model of care for individuals with CF to manage the non-pulmonary complications that persist after lung transplant. The CF Foundation virtually convened a group of international experts in CF and lung-transplant care. The committee reviewed literature and shared the post-lung transplant model of care practiced by their programs.

HOXA5 is a key regulator of class 3 semaphorins expression in the synovium of rheumatoid arthritis patients.

Objective: Class 3 semaphorins are reduced in the synovial tissue of RA patients and these proteins are involved in the pathogenesis of the disease. The aim of this study was to identify the transcription factors involved in the expression of class 3 semaphorins in the synovium of RA patients.

Methods: Protein and mRNA expression in synovial tissue from RA and individuals at risk (IAR) patients, human umbilical vein endothelial cells (HUVEC) and RA fibroblast-like synoviocytes (FLS) was determined by ELISA, immunoblotting and quantitative PCR.

Antigen specific T cells in people with obesity at five months following ChAdOx1 COVID-19 vaccination.

Background/objectives: People with obesity (PWO) face an increased risk of severe outcomes from COVID-19, including hospitalisation, ICU admission and death. Obesity has been seen to impair immune memory following vaccination against influenza, hepatitis B, tetanus, and rabies. Little is known regarding immune memory in PWO following COVID-19 adenovirus vector vaccination.

Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back.

Over the past decades, the relationship between the immune system and metabolism has become a major research focus. In this arena of immunometabolism the capacity of adipose tissue to secrete immunomodulatory molecules, including adipokines, within the underlying low-grade inflammation during obesity brought attention to the impact obesity has on the immune system. Adipokines, such as leptin and adiponectin, influence T cell differentiation into different T helper subsets and their activation during immune responses.

Association of Plaque Inflammation With Stroke Recurrence in Patients With Unproven Benefit From Carotid Revascularization.

Background And Objectives: In pooled analyses of endarterectomy trials for symptomatic carotid stenosis, several subgroups experienced no net benefit from revascularization. The validated symptomatic carotid atheroma inflammation lumen-stenosis (SCAIL) score includes stenosis severity and inflammation measured by PET and improves the identification of patients with recurrent stroke compared with lumen-stenosis alone. We investigated whether the SCAIL score improves the identification of recurrent stroke in subgroups with uncertain benefit from revascularization in endarterectomy trials.

Mucosal-associated invariant T cells are associated with insulin resistance in childhood obesity, and disrupt insulin signalling via IL-17.

Aims/hypothesis: Mucosal-associated invariant T cells (MAIT cells) are an abundant population of innate T cells. When activated, MAIT cells rapidly produce a range of cytokines, including IFNγ, TNF-α and IL-17. Several studies have implicated MAIT cells in the development of metabolic dysfunction, but the mechanisms through which this occurs are not fully understood.

Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity.

Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood. Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity.

Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function.

Obesity is one of the leading preventable causes of cancer; however, little is known about the effects of obesity on anti-tumor immunity. Here, we investigated the effects of obesity on CD8 T cells in mouse models and patients with endometrial cancer. Our findings revealed that CD8 T cell infiltration is suppressed in obesity, which was associated with a decrease in chemokine production.

Central Role of Semaphorin 3B in a Serum-Induced Arthritis Model and Reduced Levels in Patients With Rheumatoid Arthritis.

Objective: Semaphorin 3B (Sema3B) decreases the migratory and invasive capacities of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) and suppresses expression of matrix metalloproteinases. We undertook this study to examine the role of Sema3B in a mouse model of arthritis and its expression in RA patients.

Methods: Clinical responses, histologic features, and FLS function were examined in wild-type (WT) and Sema3B mice in a K/BxN serum transfer model of arthritis.

Information needs of older patients newly diagnosed with cancer.

Background: Understanding what information patients want and need is an important step in optimizing care. Therefore, we set out to collect all available evidence about the information that is most important to older patients with a new cancer diagnosis and whether or not these information needs are sufficiently addressed.

Method: A systematic literature review of Embase and Medline.

Inflammatory cytokines TNF-α and IL-17 enhance the efficacy of cystic fibrosis transmembrane conductance regulator modulators.

Without cystic fibrosis transmembrane conductance regulator-mediated (CFTR-mediated) HCO3- secretion, airway epithelia of newborns with cystic fibrosis (CF) produce an abnormally acidic airway surface liquid (ASL), and the decreased pH impairs respiratory host defenses. However, within a few months of birth, ASL pH increases to match that in non-CF airways. Although the physiological basis for the increase is unknown, this time course matches the development of inflammation in CF airways.

Survival estimates in European cystic fibrosis patients and the impact of socioeconomic factors: a retrospective registry cohort study.

Background: Median survival for cystic fibrosis (CF) patients in Europe is unknown and is likely to be influenced by socioeconomic factors. Using the European CF Society Patient Registry (ECFSPR), median survival estimates were obtained for CF patients across Europe and the impact of socioeconomic status on survival was examined.

Methods: CF subjects known to be alive and in the ECFSPR between 2010 and 2014 were included.