Search

Background: Digital health technologies have been proposed as a potential solution to improving maternal cardiovascular (CV) health in the postpartum (PP) period. In this context we performed a systematic scoping review of digital health interventions designed to improve PP CV health. Methods: We conducted a systematic review of PubMed/MEDLINE, EMBASE, CINAHL, Web of Science and the Cochrane Library. We included studies of PP women, with an intervention involving digital or mobile health (wearable devices, telemedicine, or remote monitoring). We included studies that measured an outcome related to CV health. Results: 110 full studies were reviewed for eligibility and 38 were included. Studies were categorized into 4 broad CV outcomes: blood pressure (BP), physical activity (PA), diet/weight loss and cardiometabolic markers. Digital health interventions included mobile applications, text-based coaching, interactive websites, virtual reality, wearable devices. The majority of remote BP monitoring programs (N = 5 studies) were successful in optimizing BP. 14 studies examined interventions aimed at improving PA levels of which 6/14 studies showed modest benefit at increasing PA. The majority of interventions aimed at weight loss (N = 27 studies) showed no significant benefit in terms of lowered caloric intake and/or weight loss up to 1 year PP. 6 studies examined improvements in cardiometabolic markers such as lipids and glucose levels, of which the majority showed no benefit. Conclusion: The majority of studies we reviewed found that digital health interventions such as mobile health, telemonitoring and wearable devices were feasible and had mixed effectiveness in improving postpartum CV health in the postpartum period.

Introduction: Hypertension affects approximately 50 % of patients with hypertrophic cardiomyopathy (HCM) but clinical course in adults with co-occurring HCM and hypertension is underexplored. Management may be challenging as routine anti-hypertensive medications may worsen obstructive HCM, the most common HCM phenotype. In this scoping review, we sought to synthesize the available literature related to clinical course and outcomes in adults with both conditions and to highlight knowledge gaps to inform future research directions. Methods: We searched 5 electronic databases (PubMed, CINAHL, Scopus, Embase, Web of Science) to identify peer-reviewed articles, 2011–2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review (PRISMA-ScR) guideline. Results: Eleven articles met eligibility. Adults with both conditions were older and had higher rates of obesity and diabetes than adults with HCM alone. Results related to functional class and arrhythmia were equivocal in cross-sectional studies. Only 1 article investigated changes in medical therapy among adults with both conditions. Hypertension was a predictor of worse functional class, but was not associated with all-cause mortality, heart failure-related mortality, or sudden-death. No data was found that related to common hypertension-related outcomes, including renal disease progression, nor patient-reported outcomes, including quality of life. Conclusions: Our results highlight areas for future research to improve understanding of co-occurring HCM and hypertension. These include a need for tailored approaches to medical management to optimize outcomes, evaluation of symptom burden and quality of life, and investigation of hypertension-related outcomes, like renal disease and ischemic stroke, to inform cardiovascular risk mitigation strategies.

Introduction Hypertension affects 40%–60% of adults with hypertrophic cardiomyopathy (HCM), the most common inherited cardiac condition. It can be a diagnostic confounder for HCM, contributing to delayed diagnosis. Clinically, treatment of co-occurring hypertension and HCM poses challenges as first-line and second-line antihypertensive medications are often contraindicated in HCM. The clinical course in adults with hypertension and HCM is also not well understood, and studies examining patient outcomes in this population are equivocal. In this paper, we aim to outline the protocol of a scoping review, a type of literature review, to systematically synthesise existing knowledge on adults with co-occurring HCM and hypertension, highlighting knowledge and evidence gaps, and identifying future research directions to optimise outcomes in this population.Methods and analysis This review is guided by Arksey and O’Malley’s conceptual framework on conducting scoping reviews. We will search five electronic databases (PubMed, CINAHL, Scopus, Embase and Web of Science) and reference lists of publications to identify eligible articles focusing on medical therapy, clinical course or outcomes in adults with HCM and hypertension, between 2011 and 2023. Our search strategy and presentation of results will be guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review guideline. First, two independent reviewers will screen articles, by title and abstract, followed by a full-text screen to identify eligible articles. Relevant data will be extracted and synthesised.Ethics and dissemination Ethical approval is not required for this review as it is a secondary data collection of published articles and does not involve human subject participation. We will present results of this review at relevant professional conferences and patient-centred educational events. Results will be published in a peer-reviewed journal.Trial registration number https://osf.io/cy8qb/?view_only=98197f4850584e51807ff9b62533a706.

Leader-follower autonomy (LFA) systems have so far only focused on vehicles following other vehicles. Though there have been several decades of research into this topic, there has not yet been any work on human-vehicle leader-follower systems in the known literature. We present a system in which an autonomous vehicle—our ACTor 1 platform—can follow a human leader who controls the vehicle through hand-and-body gestures. We successfully developed a modular pipeline that uses artificial intelligence/deep learning to recognize hand-and-body gestures from a user in view of the vehicle’s camera and translate those gestures into physical action by the vehicle. We demonstrate our work using our ACTor 1 platform, a modified Polaris Gem 2. Results show that our modular pipeline design reliably recognizes human body language and translates the body language into LFA commands in real time. This work has numerous applications such as material transport in industrial contexts.

Abstract Introduction Calcinosis cutis is a common complication of pediatric rheumatologic diseases. However, there is currently no consensus on first-line treatment. Bisphosphonates have been described as a successful treatment in several case studies, but most of these cases are limited to patients with isolated juvenile dermatomyositis or systemic sclerosis. Specifically, there are limited reports of their usefulness in treating overlap syndromes and mixed connective tissue disorders. Case presentation We describe the case of a 13 year-old girl with overlap syndrome with features of juvenile dermatomyositis and systemic lupus erythematosus. After 22 months of extensive immunosuppressive therapy, including monthly IVIG and Rituximab, she continued to have pain and weakness of the lower extremities. A CT scan was performed which showed significant multifocal soft tissue calcifications of the pelvis. She was started on treatment with oral alendronate with the goal of improving her calcinosis and improving her symptoms. After several months of therapy, our patient reported subjective improvement of her lower extremity pain and weakness, as well as complete resolution of abnormalities previously seen on physical examination. A repeat CT scan of the pelvis was performed after 11 months of therapy and demonstrated complete resolution of the previously seen calcinosis. Conclusions We report the successful treatment of soft tissue calcinosis with oral bisphosphonates in a patient with juvenile dermatomyositis-systemic lupus erythematosus overlap syndrome. These results provide further evidence that bisphosphonates can be used successfully to treat calcinosis cutis in pediatric rheumatologic disorders. Additionally, the results provide new evidence that they can be used specifically in juvenile dermatomyositis-systemic lupus erythematosus overlap syndrome, which has not been previously reported.

An optional diabetes module of the Behavioral Risk Factor Surveillance System was first made available to states in 1993. In 2002, 49 states administered this module. In October 2001 we asked state Diabetes Prevention and Control Program coordinators to complete a two-part questionnaire regarding the use of data from the diabetes module and their usefulness in guiding programmatic activities. Seventy percent of state coordinators reported using data from at least one module question to perform program evaluation, develop publications, and development of community interventions; 45 percent of coordinators used data from at least one module question for activities related to passage of legislation. Questions on self monitoring of blood glucose, hemoglobin A1c test, annual foot exam, annual dilated eye exam, and diabetes education were rated as highly useful by the state coordinators. The results from the optional diabetes module are widely used by states and are essential to Diabetes Prevention and Control Program activities. It is important that the optional diabetes module continue to be included in each state's yearly Behavioral Risk Factor Surveillance System. [ABSTRACT FROM AUTHOR]

People use dietary supplements to offset nutritional deficiencies and manage metabolic dysfunction. While the beneficial effect of fish proteins on glucose homeostasis is well established, the ability of fish peptides to replicate the protein findings is less clear. With financial support from a programmatic Canadian Institutes of Health Research (CIHR) Team grant, we aimed to identify salmon peptide fractions (SPFs) with the potential to mitigate metabolic dysfunction. Additionally, the grant aims included assessing whether vitamin D, a nutrient commonly found in salmon, could potentiate the beneficial effects of salmon peptides. In parallel, technologies were developed to separate and filter the isolated peptides. We employed an integrative approach that combined nutritional interventions in animal models and human subjects to identify metabolic pathways regulated by salmon peptides and other fish nutrients. This combination of interdisciplinary expertise revealed that a SPF could be a therapeutic tool used in the prevention and management of cardiometabolic diseases. Herein, we present a perspective of our CIHR funded grant that utilized a translational approach to establish the cardiometabolic health effects and mechanisms of action of fish nutrients: from animal models to clinical trials., Competing Interests: AM and LB hold patent WO 2021/108916 A1 Peptides for regulating glucose. PLM, GP, M-CV, HJ, CG and JSW declare no conflict of interest.

Background and Aims: RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases., Methods: RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank., Results: In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60)., Conclusions: PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Individuals with a higher abdominal adipose tissue accumulation are at higher risk of developing cardiometabolic diseases. For a given body mass index (BMI), women typically present lower abdominal adipose tissue accumulation compared to men. Whether abdominal adiposity is a causal driver of cardiometabolic risk, or a mere marker of ectopic fat deposition is debated., Methods: We investigated the sex-specific and sex-combined impact of height and BMI-adjusted gluteofemoral adipose tissue (GFATadj) adjusted abdominal subcutaneous adipose tissue (ASATadj) and adjusted visceral adipose tissue (VATadj) on cardiometabolic traits and diseases using Mendelian randomization., Results: Leveraging genome-wide summary statistics on GFATadj, ASATadj and VATadj from 39,076 UK Biobank participants with full-body magnetic resonance imaging available, we found that GFATadj is associated with a more favourable cardiometabolic risk profile including lower low density lipoprotein (LDL) cholesterol, triglycerides, fasting glucose, fasting insulin, liver enzyme levels and blood pressure as well as higher high density lipoprotein (HDL) cholesterol levels. GFATadj also is negatively associated with ischemic stroke, coronary artery disease, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). ASATadj is not associated with cardiometabolic traits and diseases, whereas VATadj is associated with liver fat accumulation but not with NAFLD or other cardiometabolic traits or diseases. Although the absolute effect sizes of GFATadj on LDL cholesterol were more pronounced in women compared to men, most associations did not differ by sex., Conclusions: The inability of subcutaneous fat depots to efficiently store energy substrates could be the causal factor underlying the association of visceral lipid deposition with cardiometabolic health., Competing Interests: Declaration of competing interest BJA is a consultant for Novartis, Editas Medicine, Eli Lilly and Silence Therapeutics and has received research contracts from Pfizer, Ionis Pharmaceuticals and Silence Therapeutics. The other authors have nothing to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent disease with no specific drug therapy. High-throughput metabolomics present an unprecedented opportunity to identify biomarkers and potentially causal risk factors for NAFLD. Here, we determined the impact of 21 circulating metabolites, 17 lipids, and 132 lipoprotein particle characteristics on NAFLD combining prospective observational and two-sample Mendelian randomization (MR) analyses in 121,032 UK Biobank participants. We identified several metabolic factors associated with NAFLD risk in observational and MR analyses including triglyceride-rich and high-density lipoprotein particles composition, as well as the ratio of polyunsaturated fatty acids to total fatty acids. This study, is one of the largest to investigate incident NAFLD, provides concordant observational and genetic evidence that therapies aimed at reducing circulating triglycerides and increasing large HDL particles, as well as interventions aimed at increasing polyunsaturated fatty acid content may warrant further investigation into NAFLD prevention and treatment., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Context: Hyperinsulinemia and adiposity are associated with one another, but the directionality of this relation is debated., Objective: Here, we tested the direction of the causal effects of fasting insulin (FI) levels and body fat accumulation/distribution using 2-sample bidirectional Mendelian randomization (MR)., Methods: We included summary statistics from large-scale genome-wide association studies for body mass index (BMI, n = 806 834), waist to hip ratio adjusted for BMI (WHRadjBMI, n = 694 649), abdominal subcutaneous, visceral and gluteofemoral adipose tissue (n = 38 965), FI levels (n = 98 210), pancreatic islets gene expression (n = 420), and hypothalamus gene expression (n = 155). We used inverse variance-weighted and robust MR methods that relied on statistically and biologically driven genetic instruments., Results: Both BMI and WHRadjBMI were positively associated with FI. Results were consistent across all robust MR methods and when variants mapped to the hypothalamus (presumably associated with food behavior) were included. In multivariable MR analyses, when waist circumference and BMI were mutually adjusted, the direct effect of waist circumference on FI was 2.43 times larger than the effect of BMI on FI. FI was not associated with adiposity. By contrast, using genetic instruments mapped to gene expression in pancreatic islets (presumably more specific to insulin secretion), insulin was positively associated with BMI and abdominal subcutaneous and gluteofemoral adipose tissue, but not with visceral adipose tissue., Conclusion: Although these results will need to be supported by experimental investigations, results of this MR study suggest that abdominal adiposity may be a key determinant of circulating insulin levels. Alternatively, insulin secretion may promote peripheral adipose tissue accumulation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP. Our objective was to identify blood proteins linked with AP by combining genome-wide association meta-analysis and proteome-wide Mendelian randomization (MR) studies., Methods: We performed a genome-wide association meta-analysis totalling 10,630 patients with AP and 844,679 controls and a series of inverse-variance weighted MR analyses using cis-acting variants on 4719 blood proteins from the deCODE study (N = 35,559) and 4979 blood proteins from the Fenland study (N = 10,708)., Results: The meta-analysis identified genome-wide significant variants (P <5 × 10 -8 ) at 5 loci (ABCG5/8, TWIST2, SPINK1, PRSS2 and MORC4). The proteome-wide MR analyses identified 68 unique blood proteins that may causally be associated with AP, including 29 proteins validated in both data sets. Functional annotation of these proteins confirmed expression of many proteins in metabolic tissues responsible for digestion and energy metabolism, such as the esophagus, adipose tissue, and liver as well as acinar cells of the pancreas. Genetic colocalization and investigations into the druggable genome also identified potential drug targets for AP., Conclusions: This large genome-wide association study meta-analysis for AP identified new variants linked with AP as well as several blood proteins that may be causally associated with AP. This study provides new information on the genetic architecture of this disease and identified pathways related to AP, which may be further explored as possible therapeutic targets for AP., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Faecal microbiota transplantation (FMT) in germ-free (GF) mice is a common approach to study the causal role of the gut microbiota in metabolic diseases. Lack of consideration of housing conditions post-FMT may contribute to study heterogeneity. We compared the impact of two housing strategies on the metabolic outcomes of GF mice colonised by gut microbiota from mice treated with a known gut modulator (cranberry proanthocyanidins (PAC)) or vehicle., Design: High-fat high-sucrose diet-fed GF mice underwent FMT-PAC colonisation in sterile individual positive flow ventilated cages under rigorous housing conditions and then maintained for 8 weeks either in the gnotobiotic-axenic sector or in the specific pathogen free (SPF) sector of the same animal facility., Results: Unexpectedly, 8 weeks after colonisation, we observed opposing liver phenotypes dependent on the housing environment of mice. Mice housed in the GF sector receiving the PAC gut microbiota showed a significant decrease in liver weight and hepatic triglyceride accumulation compared with control group. Conversely, exacerbated liver steatosis was observed in the FMT-PAC mice housed in the SPF sector. These phenotypic differences were associated with housing-specific profiles of colonising bacterial in the gut and of faecal metabolites., Conclusion: These results suggest that the housing environment in which gnotobiotic mice are maintained post-FMT strongly influences gut microbiota composition and function and can lead to distinctive phenotypes in recipient mice. Better standardisation of FMT experiments is needed to ensure reproducible and translatable results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with body weight but the biological relevance of most remains unexplored. Given the critical role of the brain in body weight regulation, we set out to determine whether genetic variants linked with body mass index (BMI) could be mapped to brain proteins. Using genetic colocalization, we mapped 25 loci from the largest BMI GWAS (n = 806,834) to brain protein concentrations obtained from publicly available datasets. We also performed a proteome-wide Mendelian randomization on 696 brain proteins followed by genetic colocalization and identified 35 additional brain proteins. Only a minority of these proteins (<30%) had a colocalization signal with cortex gene expression levels, highlighting the value of moving beyond gene expression levels and examining brain protein levels. In conclusion, we identified 60 unique proteins expressed in the brain that may be critical regulators of body weight in humans., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Features of the gut microbiota have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. Whether these relations underlie causal effects in humans remains to be established. We aimed to determine whether the gut microbiota influences cardiometabolic traits as well as the risk of chronic diseases and human longevity using a comprehensive 2-Sample Mendelian randomization approach. We included as exposures 10 gut-associated metabolites and pathways and 57 microbial taxa abundance. We included as outcomes nine cardiometabolic traits (fasting glucose, fasting insulin, systolic blood pressure, diastolic blood pressure, HDL cholesterol, LDL cholesterol, triglycerides, estimated glomerular filtration rate, body mass index [BMI]), eight chronic diseases previously linked with the gut microbiota in observational studies (Alzheimer's disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease), as well as parental lifespan and longevity. We found 7 associations with evidence of causality before and after sensitivity analyses, but not after multiple testing correction (1198 tests). Most effect sizes (4/7) were small. The two largest exposure-outcome effects were markedly attenuated towards the null upon inclusion of BMI or alcohol intake frequency in multivariable MR analyses. While finding robust genetic instruments for microbiota features is challenging hence potentially inflating type 2 errors, these results do not support a large causal impact of human gut microbita features on cardiometabolic traits, chronic diseases or longevity. These results also suggest that the previously documented associations between gut microbiota and human health outcomes may not always underly causal relations., (© 2023. The Author(s).)

We compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Physiological Society.)

Background: Observational studies have linked adiposity and especially abdominal adiposity to liver fat accumulation and non-alcoholic fatty liver disease. These traits are also associated with type 2 diabetes and coronary artery disease but the causal factor(s) underlying these associations remain unexplored., Methods: We used a multivariable Mendelian randomization study design to determine whether body mass index and waist circumference were causally associated with non-alcoholic fatty liver disease using publicly available genome-wide association study summary statistics of the UK Biobank ( n  = 461,460) and of non-alcoholic fatty liver disease (8434 cases and 770,180 control). A multivariable Mendelian randomization study design was also used to determine the respective causal contributions of waist circumference and liver fat ( n  = 32,858) to type 2 diabetes and coronary artery disease., Results: Using multivariable Mendelian randomization we show that waist circumference increase non-alcoholic fatty liver disease risk even when accounting for body mass index (odd ratio per 1-standard deviation increase = 2.35 95% CI = 1.31-4.22, p  = 4.2e-03), but body mass index does not increase non-alcoholic fatty liver disease risk when accounting for waist circumference (0.86 95% CI = 0.54-1.38, p  = 5.4e-01). In multivariable Mendelian randomization analyses accounting for liver fat, waist circumference remains strongly associated with both type 2 diabetes (3.27 95% CI = 2.89-3.69, p  = 3.8e-80) and coronary artery disease (1.66 95% CI = 1.54-1.8, p  = 3.4e-37)., Conclusions: These results identify waist circumference as a strong, independent, and causal contributor to non-alcoholic fatty liver disease, type 2 diabetes and coronary artery disease, thereby highlighting the importance of assessing body fat distribution for the prediction and prevention of cardiometabolic diseases., Competing Interests: Competing interestsThe authors declare the following competing interests: B.J.A. is a consultant for Novartis and Silence Therapeutics and has received research contracts from Pfizer, Ionis Pharmaceuticals and Silence Therapeutics. A.T. receives research funding from Johnson & Johnson Medical Companies, Medtronic, Bodynov, and GI Windows for studies on bariatric surgery and received consulting fees from Novo Nordisk and Bausch Health. All other authors declare no competing interests., (© The Author(s) 2022.)

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached., Significance: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599., (©2022 The Authors; Published by the American Association for Cancer Research.)

Non-alcoholic fatty liver disease (NAFLD) is a complex disease associated with premature mortality. Its diagnosis is challenging, and the identification of biomarkers causally influenced by NAFLD may be clinically useful. We aimed at identifying blood metabolites causally impacted by NAFLD using two-sample Mendelian randomization (MR) with validation in a population-based biobank. Our instrument for genetically predicted NAFLD included all independent genetic variants from a recent genome-wide association study. The outcomes included 123 blood metabolites from 24,925 individuals. After correction for multiple testing, a positive effect of NAFLD on plasma tyrosine levels but not on other metabolites was identified. This association was consistent across MR methods and was robust to outliers and pleiotropy. In observational analyses performed in the Estonian Biobank (10,809 individuals including 359 patients with NAFLD), after multivariable adjustment, tyrosine levels were positively associated with the presence of NAFLD (odds ratio per 1 SD increment = 1.23 [95% confidence interval = 1.12-1.36], p = 2.19 × 10 -5 ). In a small proof-of-concept study on bariatric surgery patients, blood tyrosine levels were higher in patients with NAFLD than without. This study revealed a potentially causal effect of NAFLD on blood tyrosine levels, suggesting it may represent a new biomarker of NAFLD.

Adiponectin is well established to mediate many beneficial metabolic effects, and this has stimulated great interest in development and validation of adiponectin receptor agonists as pharmaceutical tools. This study investigated the effects of ALY688, a peptide-based adiponectin receptor agonist, in rat L6 skeletal muscle cells. ALY688 significantly increased phosphorylation of several adiponectin downstream effectors, including AMPK, ACC, and p38MAPK, assessed by immunoblotting and immunofluorescence microscopy. Temporal analysis using cells expressing an Akt biosensor demonstrated that ALY688 enhanced insulin sensitivity. This effect was associated with increased insulin-stimulated Akt and IRS-1 phosphorylation. The functional metabolic significance of these signaling effects was examined by measuring glucose uptake in myoblasts stably overexpressing the glucose transporter GLUT4. ALY688 treatment increased basal glucose uptake and enhanced insulin-stimulated glucose uptake. In the model of high-glucose/high-insulin (HGHI)-induced insulin-resistant cells, both temporal studies using the Akt biosensor as well as immunoblotting to assess Akt and IRS-1 phosphorylation indicated that ALY688 significantly reduced insulin resistance. Importantly, we observed that ALY688 administration to high-fat high-sucrose-fed mice also improves glucose handling, validating its efficacy in vivo. In summary, these data indicate that ALY688 activates adiponectin signaling pathways in skeletal muscle, leading to improved insulin sensitivity and beneficial metabolic effects.

Hepatokines are liver-derived proteins that may influence metabolic pathways such as insulin sensitivity. Recently, Sparc-related modular calcium-binding protein 1 (SMOC1) was identified as glucose-responsive hepatokine that is dysregulated in the setting of non-alcoholic fatty liver disease (NAFLD). While SMOC1 may influence glucose-insulin homeostasis in rodents, it is unknown if SMOC1 is influenced by NAFLD in humans. It is also unknown if SMOC1 is causally associated with metabolic and disease traits in humans. Therefore, we aimed to determine the effect of NAFLD on SMOC1 gene expression in the liver and aimed to explore the potential causal associations of SMOC1 levels with NAFLD, T2D, and glycemic traits in humans. Using an RNA sequencing dataset from a cohort of 216 patients with NAFLD, we assessed SMOC1 expression levels across the NAFLD spectrum. We performed a series of bidirectional inverse-variance weighted Mendelian randomization (MR) analyses on blood SMOC1 levels using two sources of genome-wide association studies (GWAS) (Fenland study, n = 10,708 and INTERVAL study, n = 3301). We utilized GWAS summary statistics for NAFLD in 8434 cases and 770,180 controls, as well as publicly available GWAS for type 2 diabetes (T2D), body mass index (BMI), waist-to-hip ratio (WHR), fasting blood insulin (FBI), fasting blood glucose (FBG), homeostatic Model Assessment of Insulin Resistance (HOMA-B and HOMA-IR), and hemoglobin A1c (HbA1C). We found that SMOC1 expression showed no significant differences across NAFLD stages. We also identified that the top single-nucleotide polymorphism associated with blood SMOC1 levels, was associated with SMOC1 gene expression in the liver, but not in other tissues. Using MR, we did not find any evidence that genetically predicted NAFLD, T2D, and glycemic traits influenced SMOC1 levels. We also did not find evidence that blood SMOC1 levels were causally associated with T2D, NAFLD, and glycemic traits. In conclusion, the hepatokine SMOC1 does not appear to be modulated by the presence of NAFLD and may not regulate glucose-insulin homeostasis in humans. Results of this study suggest that blood factors regulating metabolism in rodents may not always translate to human biology.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked to several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluating their functional consequences. We performed a genome-wide meta-analysis of 4 cohorts of electronic health record-documented NAFLD in participants of European ancestry (8,434 cases and 770,180 controls). We identify 5 potential susceptibility loci for NAFLD (located at or near GCKR , TR1B1 , MAU2 / TM6SF2 , APOE , and PNPLA3 ). We also report a potentially causal effect of lower LPL expression in adipose tissue on NAFLD susceptibility and an effect of the FTO genotype on NAFLD. Positive genetic correlations between NAFLD and cardiometabolic diseases and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance, and coronary artery disease and negative genetic correlations with parental lifespan, socio-economic status, and acetoacetate levels are observed. This large GWAS meta-analysis reveals insights into the genetic architecture of NAFLD., Competing Interests: A.T. receives research funding from Johnson & Johnson Medical Companies, Medtronic, Bodynov, and GI Windows for studies on bariatric surgery and has received consulting fees from Novo Nordisk and Bausch Health. A.V.K. has served as a scientific advisor to Sanofi, Amgen, Maze Therapeutics, Navitor Pharmaceuticals, Sarepta Therapeutics, Novartis, Verve Therapeutics, Silence Therapeutics, Veritas International, Color Health, Third Rock Ventures, and Columbia University (NIH); has received speaking fees from Illumina, MedGenome, Amgen, and the Novartis Institute for Biomedical Research; and has received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research. B.J.A. is a consultant for Novartis and Silence Therapeutics and has received research contracts from Pfizer, Ionis Pharmaceuticals, and Silence Therapeutics., (© 2021 The Author(s).)

Objective: Lung cancer patients from ethnic minorities have poorer outcomes than their Caucasian counterparts. We compared lung cancer intervals between culturally and linguistically diverse (CALD) and Anglo-Australian patients to identify ethnic disparities., Methods: This was a prospective, observational cohort study comprising a patient survey and reviews of patients' hospital and general practice records. Across three states, 577 (407 Anglo-Australian and 170 CALD) patients were recruited and their hospital records reviewed. The survey was returned by 189 (135 Anglo-Australian and 54 CALD) patients, and a review was completed by general practitioners (GPs) of 99 (76 Anglo-Australian and 23 CALD) patients. Survival and Cox regression analyses were conducted., Results: CALD patients had longer hospital diagnostic interval [median 30 days, 95% confidence interval (CI) 26-34] than Anglo-Australian patients (median 17, 95% CI 14-20), p = 0.005, hazard ratio (HR) = 1.32 (95% CI 1.09-1.60). This difference persisted after relevant factors were taken into consideration, adjusted HR = 1.26 (95% CI 1.03-1.54, p = 0.022). CALD patients also reported longer prehospital intervals; however, these differences were not statistically significant., Conclusion: Target interventions need to be developed to address ethnic disparity in hospital diagnostic interval., (© 2021 John Wiley & Sons Ltd.)

The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and aging-associated diseases. Here, we leveraged summary statistics of a genome-wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype-Tissue Expression project. Through a combination of multi-tissue transcriptome-wide association analyses and genetic colocalization, we identified novel genes that may be associated with parental lifespan. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan and chronic diseases offering new drug repositioning opportunities such as those targeting apolipoprotein-B-containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome-wide MR analyses were used to map genetically regulated genes, proteins and metabolites with other human traits as well as the disease-related phenome in the FinnGen cohorts (n = 135,638). Altogether, this study identified new candidate genes, circulating proteins and metabolites that may influence human aging as well as potential therapeutic targets for chronic diseases that warrant further investigation., (© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Objective: This study investigated the effects of a low-dose salmon peptide fraction (SPF) and vitamin D 3 (VitD 3 ) in obese and VitD 3 -deficient mice at risk of metabolic syndrome (MetS)., Methods: Obese and VitD 3 -deficient low-density lipoprotein receptor (LDLr) -/- /apolipoprotein B100 (ApoB) 100/100 mice were treated with high-fat high-sucrose diets, with 25% of dietary proteins replaced by SPF or a nonfish protein mix (MP). The SPF and MP groups received a VitD 3 -deficient diet or a supplementation of 15,000 IU of VitD 3 per kilogram of diet. Glucose homeostasis, atherosclerosis, nonalcoholic fatty liver disease, and gut health were assessed., Results: VitD 3 supplementation increased plasma 25-hydroxyvitamin D to optimal status whereas the VitD 3 -deficient diet maintained moderate deficiency. SPF-treated groups spent more energy and accumulated less visceral fat in association with an improved adipokine profile. SPF lowered homeostatic model assessment of insulin resistance compared with MP, suggesting that SPF can improve insulin sensitivity. SPF alone blunted hepatic and colonic inflammation, whereas VitD 3 supplementation attenuated ileal inflammation. These effects were associated with changes in gut microbiota such as increased Mogibacterium and Muribaculaceae., Conclusions: SPF treatment improves MetS by modulating hepatic and gut inflammation along with gut microbiota, suggesting that SPF operates through a gut-liver axis. VitD 3 supplementation has limited influence on MetS in this model., (© 2021 The Obesity Society.)

Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that may be differentially associated with Lp(a) in patients with versus without CAVS. Our second objective was to identify genes that may be differentially regulated by exposure to high versus low Lp(a) levels in explanted aortic valves from patients with CAVS. We isolated Lp(a) from the blood of 21 patients with CAVS and 22 volunteers and performed untargeted label-free analysis of the Lp(a) proteome. We also investigated the transcriptomic signature of calcified aortic valves from patients who underwent aortic valve replacement with high versus low Lp(a) levels ( n = 118). Proteins involved in the protein activation cascade, platelet degranulation, leukocyte migration, and response to wounding may be associated with Lp(a) depending on CAVS status. The transcriptomic analysis identified genes involved in cardiac aging, chondrocyte development, and inflammation as potentially influenced by Lp(a). Our multi-omic analyses identified biological pathways through which Lp(a) may cause CAVS, as well as key molecular events that could be triggered by Lp(a) in CAVS development.

Context: The impact of galectin-3 inhibitors on nonalcoholic fatty liver diseases (NAFLD)-related outcomes is currently under investigation in randomized clinical trials. Whether there is a causal association between plasma galectin-3 levels and NAFLD is unknown., Objective: To evaluate the causal effect of circulating galectin-3 levels on NAFLD as well as >800 other human diseases., Design: Inverse variance-weighted (IVW) Mendelian randomization (MR) and phenome-wide MR., Setting: Summary statistics of genome-wide association studies., Patients: Participants of the UK Biobank, Electronic Medical Records and Genomics (eMERGE), FinnGen, Prevention of Renal and Vascular End-Stage Disease (PREVEND), and IMPROVE cohorts., Intervention: Identification of independent single-nucleotide polymorphisms (SNPs) associated with galectin-3 levels (P < 5 × 10-8) in the PREVEND (14 SNPs) and IMPROVE (3 SNPs) cohorts., Main Outcome Measures: Presence of NAFLD in a meta-analysis of genome-wide association study of the eMERGE, UK Biobank, and FinnGen cohorts (3042 NAFLD cases and 504 853 controls), as well as >800 other human diseases in the UK Biobank and FinnGen., Results: Using IVW-MR, we found no causal association between galectin-3 levels and NAFLD in the meta-analysis of the 3 cohorts or in each individual cohort. After correction for multiple testing, we found no causal association between galectin-3 levels and >800 human disease-related traits., Conclusions: This MR study revealed no causal associations between circulating galectin-3 levels and NAFLD or any other disease traits, suggesting that plasma galectin-3 levels may not be directly implicated in the pathogenesis of NAFLD or other human diseases., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cholecalciferol (D3) may improve inflammation, and thus provide protection from cardiometabolic diseases (CMD), although controversy remains. Omega-3 fatty acids (ω-3FA) may also prevent the development of CMD, but the combined effects of ω-3FA and D3 are not fully understood., Objectives: We determined the chronic independent and combined effects of D3 and ω-3FA on body weight, glucose homeostasis, and markers of inflammation in obese mice., Methods: We gave 8-week-old male C57BL/6J mice, which had been fed a high-fat, high-sucrose (HF) diet (65.5% kcal fat, 19.8% kcal carbohydrate, and 14% kcal protein) for 12 weeks, either a standard D3 dose (+SD3; 1400 IU D3/kg diet) or a high D3 dose (+HD3; 15,000 IU D3/kg diet). We fed 1 +SD3 group and 1 +HD3 group with 4.36% (w/w) fish oil (+ω-3FA; 44% eicosapentaenoic acid, 25% docosahexaenoic acid), and fed the other 2 groups with corn oil [+omega-6 fatty acids (ω-6FA)]. A fifth group was fed a low-fat (LF; 15.5% kcal) diet. LF and HF+ω-6+SD3 differences were tested by a Student's t-test and HF treatment differences were tested by a 2-way ANOVA., Results: D3 supplementation in the +HD3 groups did not significantly increase plasma total 25-hydroxyvitamin D and 25-hydroxyvitamin D3 [25(OH)D3] versus the +SD3 groups, but it increased 3-epi-25-hydroxyvitamin D3 levels by 3.4 ng/mL in the HF+ω-6+HD3 group and 4.0 ng/mL in the HF+ω-3+HD3 group, representing 30% and 70%, respectively, of the total 25(OH)D3 increase. Energy expenditure increased in those mice fed diets +ω-3FA, by 3.9% in the HF+ω-3+SD3 group and 7.4% in the HF+ω-3+HD3 group, but it did not translate into lower body weight. The glucose tolerance curves of the HF+ω-3+SD3 and HF+ω-3+HD3 groups were improved by 11% and 17%, respectively, as compared to the respective +ω-6FA groups. D3 supplementation, within the ω-3FA groups, altered the gut microbiota by increasing the abundance of S24-7 and Lachnospiraceae taxa compared to the standard dose, while within the ω-6FA groups, D3 supplementation did not modulate specific taxa., Conclusions: Overall, D3 supplementation does not prevent CMD or enhance the beneficial effects of ω-3FA in vitamin D-sufficient obese mice., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Diabetic nephropathy (DN) remains the major cause of end-stage renal disease (ESRD). We used high-fat/high-sucrose (HFHS)-fed LDLr -/- /ApoB 100/100 mice with transgenic overexpression of IGFII in pancreatic β-cells (LRKOB100/IGFII) as a model of ESRD to test whether dietary long chain omega-3 polyunsaturated fatty acids LCω3FA-rich fish oil (FO) could prevent ESRD development. We further evaluated the potential of docosahexaenoic acid (DHA)-derived pro-resolving lipid mediators, 17-hydroxy-DHA (17-HDHA) and Protectin DX (PDX), to reverse established ESRD damage. HFHS-fed vehicle-treated LRKOB100/IGFII mice developed severe kidney dysfunction leading to ESRD, as revealed by advanced glomerular fibrosis and mesangial expansion along with reduced percent survival. The kidney failure outcome was associated with cardiac dysfunction, revealed by reduced heart rate and prolonged diastolic and systolic time. Dietary FO prevented kidney damage, lean mass loss, cardiac dysfunction, and death. 17-HDHA reduced podocyte foot process effacement while PDX treatment alleviated kidney fibrosis and mesangial expansion as compared to vehicle treatment. Only PDX therapy was effective at preserving the heart function and survival rate. These results show that dietary LCω3FA intake can prevent ESRD and cardiac dysfunction in LRKOB100/IGFII diabetic mice. Our data further reveals that PDX can protect against renal failure and cardiac dysfunction, offering a potential new therapeutic strategy against ESRD., (© 2021 Federation of American Societies for Experimental Biology.)

Obesity and diabetes are strongly associated not only with fatty liver but also cognitive dysfunction. Moreover, their presence, particularly in midlife, is recognized as a risk factor for Alzheimer's disease (AD). AD, the most common cause of dementia, is increasingly considered as a metabolic disease, although underlying pathogenic mechanisms remain unclear. The liver plays a major role in maintaining glucose and lipid homeostasis, as well as in clearing the AD neuropathogenic factor amyloid-β (Aβ) and in metabolizing cerebrosterol, a cerebral-derived oxysterol proposed as an AD biomarker. We hypothesized that liver impairment induced by obesity contributes to AD pathogenesis. We show that the AD triple transgenic mouse model (3xTg-AD) fed a chow diet presents a hepatic phenotype similar to nontransgenic controls (NTg) at 15 months of age. A high-fat diet (HFD), started at the age of 6 months and continued for 9 months, until sacrifice, induced hepatic steatosis in NTg, but not in 3xTg-AD mice, whereas HFD did not induce changes in hepatic fatty acid oxidation, de novo lipogenesis, and gluconeogenesis. HFD-induced obesity was associated with a reduction of insulin-degrading enzyme, one of the main hepatic enzymes responsible for Aβ clearance. The hepatic rate of cerebrosterol glucuronidation was lower in obese 3xTg-AD than in nonobese controls ( P  < 0.05) and higher compared with obese NTg ( P  < 0.05), although circulating levels remained unchanged. Conclusion: Modulation of hepatic lipids, Aβ, and cerebrosterol metabolism in obese 3xTg-AD mice differs from control mice. This study sheds light on the liver-brain axis, showing that the chronic presence of NAFLD and changes in liver function affect peripheral AD features and should be considered during development of biomarkers or AD therapeutic targets., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Lipoprotein(a) (Lp[a]), which consists of a low-density lipoprotein (LDL) bound to apolipoprotein(a), is one of the strongest genetic risk factors for atherosclerotic cardiovascular diseases. Few studies have performed hypothesis-free direct comparisons of the Lp(a) and the LDL proteomes. Our objectives were to compare the Lp(a) and the LDL proteomic profiles and to evaluate the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile., Methods: We performed a label-free analysis of the Lp(a) and LDL proteomic profiles of healthy volunteers in a discovery (n = 6) and a replication (n = 9) phase. We performed inverse variance weighted Mendelian randomization to document the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile of participants of the INTERVAL study., Results: We identified 15 proteins that were more abundant on Lp(a) compared with LDL ( serping1 , pi16 , itih1 , itih2 , itih3 , pon1 , podxl , cd44 , cp , ptprg , vtn , pcsk9 , igfals , vcam1 , and ttr ). We found no proteins that were more abundant on LDL compared with Lp(a). After correction for multiple testing, lifelong exposure to elevated LDL cholesterol levels was associated with the variation of 18 plasma proteins whereas Lp(a) did not appear to influence the plasma proteome., Conclusions: Results of this study highlight marked differences in the proteome of Lp(a) and LDL as well as in the effect of lifelong exposure to elevated LDL cholesterol or Lp(a) on the plasma proteomic profile., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

Our objectives were to determine whether autotaxin (ATX) is transported by lipoprotein(a) [Lp(a)] in human plasma and if could be used as a biomarker of calcific aortic valve stenosis (CAVS). We first found that ATX activity was higher in Lp(a) compared to low-density lipoprotein fractions in isolated fractions of 10 healthy participants. We developed a specific assay to measure ATX-Lp(a) in 88 patients with CAVS and 144 controls without CAVS. In a multivariable model corrected for CAVS risk factors, ATX-Lp(a) was associated with CAVS (p = 0.003). We concluded that ATX is preferentially transported by Lp(a) and might represent a novel biomarker for CAVS., (© 2020 The Authors.)

Prenatal exposure to persistent organic pollutants (POPs) has been associated with the development of metabolic syndrome-related diseases in offspring. According to epidemiological studies, father's transmission of environmental effects in addition to mother's can influence offspring health. Moreover, maternal prenatal dietary folic acid (FA) may beneficially impact offspring health. The objective is to investigate whether prenatal FA supplementation can overcome the deleterious effects of prenatal exposure to POPs on lipid homeostasis and inflammation in three generations of male rat descendants through the paternal lineage. Female Sprague-Dawley rats (F0) were exposed to a POPs mixture (or corn oil) +/- FA supplementation for 9 weeks before and during gestation. F1 and F2 males were mated with untreated females. Plasma and hepatic lipids were measured in F1, F2, and F3 males after 12-h fast. Gene expression of inflammatory cytokines was determined by qPCR in epididymal adipose tissue. In F1 males, prenatal POPs exposure increased plasma lipids at 14 weeks old and hepatic lipids at 28 weeks old and prenatal FA supplementation decreased plasma total cholesterol at 14 weeks old. Prenatal POPs exposure decreased plasma triglycerides at 14 weeks old in F2 males. No change was observed in inflammatory markers. Our results show an impact of the paternal lineage on lipid homeostasis in rats up to the F2 male generation. FA supplementation of the F0 diet, regardless of POPs exposure, lowered plasma cholesterol in F1 males but failed to attenuate the deleterious effects of prenatal POPs exposure on plasma and hepatic lipids in F1 males.

Objectives: Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK have been identified in many types of cancer, including non-small cell lung cancer (NSCLC). Data in malignant pleural mesothelioma (MPM), lung neuroendocrine tumors (NETs) and small-cell lung cancer (SCLC) are lacking. Given the activity of NTRK, ROS-1 and ALK inhibitors in tumors harboring gene fusions, we sought to explore such rearrangements in these less common tumors in addition to NSCLC., Methods: Archival tumor tissue from patients with MPM, lung NETs, SCLC and NSCLC were used to create tissue microarrays. Immunohistochemistry (IHC) was performed using a cocktail of antibodies against TRK, ROS1 and ALK. IHC positive samples underwent RNA sequencing using the ArcherDX FusionPlex CTL diagnostic assay. Clinical data were obtained through retrospective chart review., Results: We performed IHC on 1116 samples: 335 MPMs, 522 NSCLCs, 105 SCLCs and 154 lung NETs. There were 23 IHC positive cases (2.1%) including eight MPMs (2.4%), eight NETs (5.2%), five SCLC (4.8%) and two NSCLC (0.4%). The following fusions were detected: one MPM with an NTRK ex10-TPM3 ex8, another MPM with an ALK ex20-EML4ex13, one lung intermediate-grade NET (atypical carcinoid) with an ALK ex20-EML4 ex6/intron6, and two NSCLCs with an ALK ex20-EML4 ex6/intron6 rearrangement. None of the patients received targeted treatment., Conclusions: To our knowledge, we report for the first time NTRK and ALK rearrangements in a small subset of MPM. An ALK rearrangement was also detected in lung intermediate-grade NET (or atypical carcinoid). Our data suggest that IHC could be a useful screening test in such patients to ensure that all therapeutic strategies including targeted therapy are utilized., Competing Interests: Declaration of Competing Interest Dr. Leal has received investigation grants from MSD, Roche, Boheringer Ingelheim, Pfizer, Astra Zeneca and BMS; and has received personal fees from MSD, Roche, Boheringer Ingelheim, Pfizer, Astra Zeneca, BMS, Sanofi, Elly-Lilly and Tecnofarma. All this is outside of the submitted work. Dr. Leong has received personal fees from Pfizer and Astra Zeneca; has received non-financial support from Biocardis Idylla and Roche, all outside of the submitted work. Dr. Rivalland has received personal fees from Astra Zeneca and MSD, and non-financial support from Pfizer, all outside of the submitted work. Dr. Mitchell has received grants from Astra Zeneca and BMS; has received personal fees from Astra Zeneca, BMS, Amgen, Roche, MSD, Merck, Boheringer Ingelheim and Pfizer; and non-financial support from Astra Zeneca, BMS and Roche. Dr. John has received personal fees from Ignyta, Roche, Astra Zeneca, Novartis, Pfizer, BMS and Merck, all outside of the submitted work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Poor dietary habits contribute to the obesity pandemic and related cardiovascular diseases but the respective impact of high saturated fat versus added sugar consumption remains debated. Herein, we aimed to disentangle the individual role of dietary fat versus sugar in cardiometabolic disease progression., Methods: We fed pro-atherogenic LDLr -/- ApoB 100/100 mice either a low-fat/high-sucrose (LFHS) or a high-fat/low-sucrose (HFLS) diet for 24 weeks. Weekly body weight gain was registered. 16S rRNA gene-based gut microbial analysis was performed to investigate gut microbial modulations. Intraperitoneal insulin (ipITT) and oral glucose tolerance test (oGTT) were conducted to assess glucose homeostasis and insulin sensitivity. Cytokines were assessed in fasted plasma, epididymal white adipose tissue and liver lysates. Heart function was evaluated by echocardiography. Aortic atheroma lesions were quantified according to the en face technique., Results: HFLS feeding increased obesity, insulin resistance and dyslipidemia compared to LFHS feeding. Conversely, high sucrose consumption decreased gut microbial diversity while augmenting inflammation and the adaptative immune defense against metabolic endotoxemia and reduced macrophage cholesterol efflux capacity. This led to more severe cardiovascular complications as revealed by remarkably high level of atherosclerotic lesions and the early development of cardiac dysfunction in LFHS vs HFLS fed mice., Conclusions: We uncoupled obesity-associated insulin resistance from cardiovascular diseases and provided novel evidence that dietary sucrose, not fat, is the main driver of metabolic inflammation accelerating severe atherosclerosis in hyperlipidemic mice., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Hepatokines are proteins secreted by the liver that impact the functions of the liver and various tissues through autocrine, paracrine, and endocrine signaling. Recently, Tsukushi (TSK) was identified as a new hepatokine that is induced by obesity and cold exposure. It was proposed that TSK controls sympathetic innervation and thermogenesis in brown adipose tissue (BAT) and that loss of TSK protects against diet-induced obesity and improves glucose homeostasis. Here we report the impact of deleting and/or overexpressing TSK on BAT thermogenic capacity, body weight regulation, and glucose homeostasis., Methods: We measured the expression of thermogenic genes and markers of BAT innervation and activation in TSK-null and TSK-overexpressing mice. Body weight, body temperature, and parameters of glucose homeostasis were also assessed in the context of TSK loss and overexpression., Results: The loss of TSK did not affect the thermogenic activation of BAT. We found that TSK-null mice were not protected against the development of obesity and did not show improvement in glucose tolerance. The overexpression of TSK also failed to modulate thermogenesis, body weight gain, and glucose homeostasis in mice., Conclusions: TSK is not a significant regulator of BAT thermogenesis and is unlikely to represent an effective target to prevent obesity and improve glucose homeostasis., (Copyright © 2019 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) prevails in obesity and is linked to several health complications including dyslipidemia and atherosclerosis. How exactly NAFLD induces atherogenic dyslipidemia to promote cardiovascular diseases is still elusive. Here, we identify Tsukushi (TSK) as a hepatokine induced in response to NAFLD. We show that both endoplasmic reticulum stress and inflammation promote the expression and release of TSK in mice. In humans, hepatic TSK expression is also associated with steatosis, and its circulating levels are markedly increased in patients suffering from acetaminophen-induced acute liver failure (ALF), a condition linked to severe hepatic inflammation. In these patients, elevated blood TSK levels were associated with decreased transplant-free survival at hospital discharge, suggesting that TSK could have a prognostic significance. Gain- and loss-of-function studies in mice revealed that TSK impacts systemic cholesterol homeostasis. TSK reduces circulating HDL cholesterol, lowers cholesterol efflux capacity, and decreases cholesterol-to-bile acid conversion in the liver. Our data identify the hepatokine TSK as a blood biomarker of liver stress that could link NAFLD to the development of atherogenic dyslipidemia and atherosclerosis.

Autotaxin (ATX), an adipose tissue-derived lysophospholipase, has been involved in the pathophysiology of cardiometabolic diseases. The impact of bariatric surgery on circulating ATX levels is unknown. We examined the short- (24 h, 5 days) and longer-term (6 and 12 months) impact of bariatric surgery; as well as the short-term effect of caloric restriction (CR) on plasma ATX levels in patients with severe obesity. We measured ATX levels in 69 men and women (mean age: 41 ± 11 years, body mass index: 49.8 ± 7.1 kg/m 2 ), before and after biliopancreatic diversion with duodenal switch surgery (BPD-DS) as well as in a control group (patients with severe obesity without surgery; n = 34). We also measured ATX levels in seven patients with severe obesity and type 2 diabetes who underwent a 3-day CR protocol before their BPD-DS. At baseline, ATX levels were positively associated with body mass index, fat mass, insulin resistance (HOMA-IR) as well as insulin and leptin levels and negatively with fat-free mass. ATX concentrations decreased 26.2% at 24 h after BPD-DS (342.9 ± 152.3 pg/mL to 253.2 ± 68.9 pg/mL, P < 0.0001) and by 16.4% at 12 months after BPD-DS (342.9 ± 152.3 pg/mL to 286.8 ± 182.6 pg/mL, P = 0.04). ATX concentrations were unchanged during follow-up in the control group (P = 0.4), and not influenced by short-term CR. In patients with severe obesity, bariatric surgery induced a rapid and sustained decrease in plasma ATX levels. Acute changes in ATX may not be explained by bariatric surgery-induced CR., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Purpose: Few large-scale studies have investigated sex differences in cancer survival and little is known about their temporal and age-related patterns., Methods: We used cancer registry data for first primary cancers diagnosed between 1982 and 2015 in Victoria, Australia. Cases were followed until the end of 2015 through linkage to death registries. Differences in survival were assessed for 25 cancers using the Pohar-Perme estimator of net survival and the excess mortality rate ratio (EMRR) adjusting for age and year of diagnosis., Results: Five-year net survival for all cancers combined was lower for men (47.1%; 95% CI 46.9-47.4) than women (52.0%; 95% CI 51.7-52.3); EMRR 1.13 (95% CI 1.12-1.14; p < 0.001). A survival disadvantage for men was observed for 11 cancers: head and neck, esophagus, colorectum, pancreas, lung, bone, melanoma, mesothelioma, kidney, thyroid, and non-Hodgkin lymphoma. In contrast, women had lower survival from cancers of the bladder, renal pelvis, and ureter. For the majority of cancers with survival differences, the EMRR decreased with increasing age at diagnosis; for colorectal, esophageal, and kidney cancer, the EMRR increased with time since diagnosis., Conclusion: Identifying the underlying reasons behind sex differences in cancer survival is necessary to address inequalities, which may improve outcomes for men and women.

In the original publication of the article, the concluding paragraph of the Discussion section was inadvertently missed and is provided below.