Liver fibrosis is associated with left ventricular remodeling: insight into the liver-heart axis.

OBJECTIVE: In nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the strongest predictor of adverse outcomes. We sought to investigate the relationship between liver fibrosis and cardiac remodeling in participants from the general population using magnetic resonance imaging (MRI), as well as explore potential mechanistic pathways by analyzing circulating cardiovascular biomarkers. METHODS: In this cross-sectional study, we prospectively included participants with type 2 diabetes and individually matched controls from the SCAPIS (Swedish CArdioPulmonary bioImage Study) cohort in Linköping, Sweden. Between November 2017 and July 2018, participants underwent MRI at 1.5 Tesla for quantification of liver proton density fat fraction (spectroscopy), liver fibrosis (stiffness from elastography), left ventricular (LV) structure and function, as well as myocardial native T1 mapping. We analyzed 278 circulating cardiovascular biomarkers using a Bayesian statistical approach. RESULTS: In total, 92 participants were enrolled (mean age 59.5 ± 4.6 years, 32 women). The mean liver stiffness was 2.1 ± 0.4 kPa. 53 participants displayed hepatic steatosis. LV concentricity increased across quartiles of liver stiffness. Neither liver fat nor liver stiffness displayed any relationships to myocardial tissue characteristics (native T1). In a regression analysis, liver stiffness was related to increased LV concentricity. This association was independent of diabetes and liver fat (Beta = 0.26, p = 0.0053), but was attenuated (Beta = 0.17, p = 0.077) when also adjusting for circulating levels of interleukin-1 receptor type 2. CONCLUSION: MRI reveals that liver fibrosis is associated to structural LV remodeling, in terms of increased concentricity, in participants from the general population. This relationship could involve the interleukin-1 signaling. CLINICAL RELEVANCE STATEMENT: Liver fibrosis may be considered a cardiovascular risk factor in patients without cirrhosis. Further research on the mechanisms that link liver fibrosis to left ventricular concentricity may reveal potential therapeutic targets in patients with non-alcoholic fatty liver disease (NAFLD). KEY POINTS: Previously, studies on liver fibrosis and cardiac remodeling have focused on advanced stages of liver fibrosis. Liver fibrosis is associated with left ventricular (LV) concentricity and may relate to interleukin-1 receptor type 2. Interleukin-1 signaling is a potential mechanistic interlink between early liver fibrosis and LV remodeling.

A unified framework for prediction of liver steatosis dynamics in response to different diet and drug interventions.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder, characterized by the accumulation of excess fat in the liver, and is a driving factor for various severe liver diseases. These multi-factorial and multi-timescale changes are observed in different clinical studies, but these studies have not been integrated into a unified framework. In this study, we aim to present such a unified framework in the form of a dynamic mathematical model. METHODS: For model training and validation, we collected data for dietary or drug-induced interventions aimed at reducing or increasing liver fat. The model was formulated using ordinary differential equations (ODEs) and the mathematical analysis, model simulation, model formulation and the model parameter estimation were all performed in MATLAB. RESULTS: Our mathematical model describes accumulation of fat in the liver and predicts changes in lipid fluxes induced by both dietary and drug interventions. The model is validated using data from a wide range of drug and dietary intervention studies and can predict both short-term (days) and long-term (weeks) changes in liver fat. Importantly, the model computes the contribution of each individual lipid flux to the total liver fat dynamics. Furthermore, the model can be combined with an established bodyweight model, to simulate even longer scenarios (years), also including the effects of insulin resistance and body weight. To help prepare for corresponding eHealth applications, we also present a way to visualize the simulated changes, using dynamically changing lipid droplets, seen in images of liver biopsies. CONCLUSION: In conclusion, we believe that the minimal model presented herein might be a useful tool for future applications, and to further integrate and understand data regarding changes in dietary and drug induced changes in ectopic TAG in the liver. With further development and validation, the minimal model could be used as a disease progression model for steatosis.

A physiologically-based digital twin for alcohol consumption-predicting real-life drinking responses and long-term plasma PEth.

Alcohol consumption is associated with a wide variety of preventable health complications and is a major risk factor for all-cause mortality in the age group 15-47 years. To reduce dangerous drinking behavior, eHealth applications have shown promise. A particularly interesting potential lies in the combination of eHealth apps with mathematical models. However, existing mathematical models do not consider real-life situations, such as combined intake of meals and beverages, and do not connect drinking to clinical markers, such as phosphatidylethanol (PEth). Herein, we present such a model which can simulate real-life situations and connect drinking to long-term markers. The new model can accurately describe both estimation data according to a χ2 -test (187.0 < Tχ2 = 226.4) and independent validation data (70.8 < Tχ2 = 93.5). The model can also be personalized using anthropometric data from a specific individual and can thus be used as a physiologically-based digital twin. This twin is also able to connect short-term consumption of alcohol to the long-term dynamics of PEth levels in the blood, a clinical biomarker of alcohol consumption. Here we illustrate how connecting short-term consumption to long-term markers allows for a new way to determine patient alcohol consumption from measured PEth levels. An additional use case of the twin could include the combined evaluation of patient-reported AUDIT forms and measured PEth levels. Finally, we integrated the new model into an eHealth application, which could help guide individual users or clinicians to help reduce dangerous drinking.

Altered probe pressure and body position increase diagnostic accuracy for men and women in detecting hepatic steatosis using quantitative ultrasound.

OBJECTIVES: To evaluate the diagnostic performance of ultrasound guided attenuation parameter (UGAP) for evaluating liver fat content with different probe forces and body positions, in relation to sex, and compared with proton density fat fraction (PDFF). METHODS: We prospectively enrolled a metabolic dysfunction-associated steatotic liver disease (MASLD) cohort that underwent UGAP and PDFF in the autumn of 2022. Mean UGAP values were obtained in supine and 30° left decubitus body position with normal 4 N and increased 30 N probe force. The diagnostic performance was evaluated by the area under the receiver operating characteristic curve (AUC). RESULTS: Among 60 individuals (mean age 52.9 years, SD 12.9; 30 men), we found the best diagnostic performance with increased probe force in 30° left decubitus position (AUC 0.90; 95% CI 0.82-0.98) with a cut-off of 0.58 dB/cm/MHz. For men, the best performance was in supine (AUC 0.91; 95% CI 0.81-1.00) with a cut-off of 0.60 dB/cm/MHz, and for women, 30° left decubitus position (AUC 0.93; 95% CI 0.83-1.00), with a cut-off 0.56 dB/cm/MHz, and increased 30 N probe force for both genders. No difference was in the mean UGAP value when altering body position. UGAP showed good to excellent intra-reproducibility (Intra-class correlation 0.872; 95% CI 0.794-0.921). CONCLUSION: UGAP provides excellent diagnostic performance to detect liver fat content in metabolic dysfunction-associated steatotic liver diseases, with good to excellent intra-reproducibility. Regardless of sex, the highest diagnostic accuracy is achieved with increased probe force with men in supine and women in 30° left decubitus position, yielding different cut-offs. CLINICAL RELEVANCE STATEMENT: The ultrasound method ultrasound-guided attenuation parameter shows excellent diagnostic accuracy and performs with good to excellent reproducibility. There is a possibility to alter body position and increase probe pressure, and different performances for men and women should be considered for the highest accuracy. KEY POINTS: • There is a possibility to alter body position when performing the ultrasound method ultrasound-guided attenuation parameter. • Increase probe pressure for the highest accuracy. • Different performances for men and women should be considered.

Low-dose acetylsalicylic acid reduces local inflammation and tissue perfusion in dense breast tissue in postmenopausal women.

PURPOSE: One major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to ~ 30% of all breast cancer. Prevention targeting dense breast tissue has the potential to improve breast cancer mortality and morbidity. Anti-estrogens, which may be associated with severe side-effects, can be used for prevention of breast cancer in women with high risk of the disease per se. However, no preventive therapy targeting dense breasts is currently available. Inflammation is a hallmark of cancer. Although the biological mechanisms involved in the increased risk of cancer in dense breasts is not yet fully understood, high mammographic density has been associated with increased inflammation. We investigated whether low-dose acetylsalicylic acid (ASA) affects local breast tissue inflammation and/or structural and dynamic changes in dense breasts. METHODS: Postmenopausal women with mammographic dense breasts on their regular mammography screen were identified. A total of 53 women were randomized to receive ASA 160 mg/day or no treatment for 6 months. Magnetic resonance imaging (MRI) was performed before and after 6 months for a sophisticated and continuous measure breast density by calculating lean tissue fraction (LTF). Additionally, dynamic quantifications including tissue perfusion were performed. Microdialysis for sampling of proteins in vivo from breasts and abdominal subcutaneous fat, as a measure of systemic effects, before and after 6 months were performed. A panel of 92 inflammatory proteins were quantified in the microdialysates using proximity extension assay. RESULTS: After correction for false discovery rate, 20 of the 92 inflammatory proteins were significantly decreased in breast tissue after ASA treatment, whereas no systemic effects were detected. In the no-treatment group, protein levels were unaffected. Breast density, measured by LTF on MRI, were unaffected in both groups. ASA significantly decreased the perfusion rate. The perfusion rate correlated positively with local breast tissue concentration of VEGF. CONCLUSIONS: ASA may shape the local breast tissue microenvironment into an anti-tumorigenic state. Trials investigating the effects of low-dose ASA and risk of primary breast cancer among postmenopausal women with maintained high mammographic density are warranted. Trial registration EudraCT: 2017-000317-22.

Pain and the biochemistry of fibromyalgia: patterns of peripheral cytokines and chemokines contribute to the differentiation between fibromyalgia and controls and are associated with pain, fat infiltration and content.

Objectives: This explorative study analyses interrelationships between peripheral compounds in saliva, plasma, and muscles together with body composition variables in healthy subjects and in fibromyalgia patients (FM). There is a need to better understand the extent cytokines and chemokines are associated with body composition and which cytokines and chemokines differentiate FM from healthy controls. Methods: Here, 32 female FM patients and 30 age-matched female healthy controls underwent a clinical examination that included blood sample, saliva samples, and pain threshold tests. In addition, the subjects completed a health questionnaire. From these blood and saliva samples, a panel of 68 mainly cytokines and chemokines were determined. Microdialysis of trapezius and erector spinae muscles, phosphorus-31 magnetic resonance spectroscopy of erector spinae muscle, and whole-body magnetic resonance imaging for determination of body composition (BC)-i.e., muscle volume, fat content and infiltration-were also performed. Results: After standardizing BC measurements to remove the confounding effect of Body Mass Index, fat infiltration and content are generally increased, and fat-free muscle volume is decreased in FM. Mainly saliva proteins differentiated FM from controls. When including all investigated compounds and BC variables, fat infiltration and content variables were most important, followed by muscle compounds and cytokines and chemokines from saliva and plasma. Various plasma proteins correlated positively with pain intensity in FM and negatively with pain thresholds in all subjects taken together. A mix of increased plasma cytokines and chemokines correlated with an index covering fat infiltration and content in different tissues. When muscle compounds were included in the analysis, several of these were identified as the most important regressors, although many plasma and saliva proteins remained significant. Discussion: Peripheral factors were important for group differentiation between FM and controls. In saliva (but not plasma), cytokines and chemokines were significantly associated with group membership as saliva compounds were increased in FM. The importance of peripheral factors for group differentiation increased when muscle compounds and body composition variables were also included. Plasma proteins were important for pain intensity and sensitivity. Cytokines and chemokines mainly from plasma were also significantly and positively associated with a fat infiltration and content index. Conclusion: Our findings of associations between cytokines and chemokines and fat infiltration and content in different tissues confirm that inflammation and immune factors are secreted from adipose tissue. FM is clearly characterized by complex interactions between peripheral tissues and the peripheral and central nervous systems, including nociceptive, immune, and neuroendocrine processes.

A multi-scale digital twin for adiposity-driven insulin resistance in humans: diet and drug effects.

BACKGROUND: The increased prevalence of insulin resistance is one of the major health risks in society today. Insulin resistance involves both short-term dynamics, such as altered meal responses, and long-term dynamics, such as the development of type 2 diabetes. Insulin resistance also occurs on different physiological levels, ranging from disease phenotypes to organ-organ communication and intracellular signaling. To better understand the progression of insulin resistance, an analysis method is needed that can combine different timescales and physiological levels. One such method is digital twins, consisting of combined mechanistic mathematical models. We have previously developed a model for short-term glucose homeostasis and intracellular insulin signaling, and there exist long-term weight regulation models. Herein, we combine these models into a first interconnected digital twin for the progression of insulin resistance in humans. METHODS: The model is based on ordinary differential equations representing biochemical and physiological processes, in which unknown parameters were fitted to data using a MATLAB toolbox. RESULTS: The interconnected twin correctly predicts independent data from a weight increase study, both for weight-changes, fasting plasma insulin and glucose levels, and intracellular insulin signaling. Similarly, the model can predict independent weight-change data in a weight loss study with the weight loss drug topiramate. The model can also predict non-measured variables. CONCLUSIONS: The model presented herein constitutes the basis for a new digital twin technology, which in the future could be used to aid medical pedagogy and increase motivation and compliance and thus aid in the prevention and treatment of insulin resistance.

A rapid, non-invasive, clinical surveillance for CachExia, sarcopenia, portal hypertension, and hepatocellular carcinoma in end-stage liver disease: the ACCESS-ESLD study protocol.

BACKGROUND: Liver cirrhosis, the advanced stage of many chronic liver diseases, is associated with escalated risks of liver-related complications like decompensation and hepatocellular carcinoma (HCC). Morbidity and mortality in cirrhosis patients are linked to portal hypertension, sarcopenia, and hepatocellular carcinoma. Although conventional cirrhosis management centered on treating complications, contemporary approaches prioritize preemptive measures. This study aims to formulate novel blood- and imaging-centric methodologies for monitoring liver cirrhosis patients. METHODS: In this prospective study, 150 liver cirrhosis patients will be enrolled from three Swedish liver clinics. Their conditions will be assessed through extensive blood-based markers and magnetic resonance imaging (MRI). The MRI protocol encompasses body composition profile with Muscle Assement Score, portal flow assessment, magnet resonance elastography, and a abbreviated MRI for HCC screening. Evaluation of lifestyle, muscular strength, physical performance, body composition, and quality of life will be conducted. Additionally, DNA, serum, and plasma biobanking will facilitate future investigations. DISCUSSION: The anticipated outcomes involve the identification and validation of non-invasive blood- and imaging-oriented biomarkers, enhancing the care paradigm for liver cirrhosis patients. Notably, the temporal evolution of these biomarkers will be crucial for understanding dynamic changes. TRIAL REGISTRATION: Clinicaltrials.gov, registration identifier NCT05502198. Registered on 16 August 2022. Link: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05502198 .

Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Radiation-dependent demyelination in normal appearing white matter in glioma patients, determined using quantitative magnetic resonance imaging.

Background and purpose: A brain tumour, especially a glioma, is a rare disease; it is challenging to treat and the prognosis is often poor. Routine care includes surgery and concomitant chemoradiotherapy (CRT). Diagnostic work-up and treatment effects are typically evaluated using magnetic resonance imaging (MRI). Quantitative MRI (qMRI), unlike conventional MRI, has the advantage of providing tissue-specific relaxation rates and proton density. The purpose is to detect changes in normal appearing white matter (NAWM) in brain tumour patients after CRT using qMRI. Materials & methods: NAWM was analysed in 10 patients, in 83 MR examinations performed before and after surgery and after CRT. Relaxation rates R1 and R2, the proton density (PD) and the concentration of myelin (cMy) were calculated from the qMRI scans and analysed in correlation to radiation dose and time after treatment. Results: A significant decrease in cMy between pre-treatment imaging and first follow-up and an increase in PD were observed. For low doses (less than 30 Gy) PD and cMy returned to baseline (=pre-operative status), while for high doses (>30 Gy) the change increased during the full extent of the follow-up period. No difference could be established for R1. For R2 an increase was observed during the first year, which then gradually returned to baseline. For R2, stronger effects were seen as a consequence of higher absorbed doses. Conclusion: In the long-term follow-up for glioma patients, qMRI is a powerful tool for detecting small changes, such as a decrease of myelin concentration, in NAWM after CRT.

Haemodynamic effects of hypertension and type 2 diabetes: Insights from a 4D flow MRI-based personalized cardiovascular mathematical model.

Type 2 diabetes (T2D) and hypertension increase the risk of cardiovascular diseases mediated by whole-body changes to metabolism, cardiovascular structure and haemodynamics. The haemodynamic changes related to hypertension and T2D are complex and subject-specific, however, and not fully understood. We aimed to investigate the haemodynamic mechanisms in T2D and hypertension by comparing the haemodynamics between healthy controls and subjects with T2D, hypertension, or both. For all subjects, we combined 4D flow magnetic resonance imaging data, brachial blood pressure and a cardiovascular mathematical model to create a comprehensive subject-specific analysis of central haemodynamics. When comparing the subject-specific haemodynamic parameters between the four groups, the predominant haemodynamic difference is impaired left ventricular relaxation in subjects with both T2D and hypertension compared to subjects with only T2D, only hypertension and controls. The impaired relaxation indicates that, in this cohort, the long-term changes in haemodynamic load of co-existing T2D and hypertension cause diastolic dysfunction demonstrable at rest, whereas either disease on its own does not. However, through subject-specific predictions of impaired relaxation, we show that altered relaxation alone is not enough to explain the subject-specific and group-related differences; instead, a combination of parameters is affected in T2D and hypertension. These results confirm previous studies that reported more adverse effects from the combination of T2D and hypertension compared to either disease on its own. Furthermore, this shows the potential of personalized cardiovascular models in providing haemodynamic mechanistic insights and subject-specific predictions that could aid in the understanding and treatment planning of patients with T2D and hypertension. KEY POINTS: The combination of 4D flow magnetic resonance imaging data and a cardiovascular mathematical model allows for a comprehensive analysis of subject-specific haemodynamic parameters that otherwise cannot be derived non-invasively. Using this combination, we show that diastolic dysfunction in subjects with both type 2 diabetes (T2D) and hypertension is the main group-level difference between controls, subjects with T2D, subjects with hypertension, and subjects with both T2D and hypertension. These results suggest that, in this relatively healthy population, the additional load of both hypertension and T2D affects the haemodynamic function of the left ventricle, whereas each disease on its own is not enough to cause significant effects under resting conditions. Finally, using the subject-specific model, we show that the haemodynamic effects of diastolic dysfunction alone are not sufficient to explain all the observed haemodynamic differences. Instead, additional subject-specific variations in cardiac and vascular function combine to explain the complex haemodynamics of subjects affected by hypertension and/or T2D.

Breast density and estradiol are associated with distinct different expression patterns of metabolic proteins in normal human breast tissue in vivo.

Background: Breast density and exposure to sex steroids are major risk factors for breast cancer. The local microenvironment plays an essential role in progression of breast cancer. Metabolic adaption is a major hallmark of cancer. Whether proteins from the extracellular space regulating metabolism are affected in breast cancer, dense breasts or by estrogen exposure are not yet fully elucidated. Methods: Women with breast cancer, postmenopausal women with normal breast tissue with varying breast density or premenopausal women with breasts exposed to high levels of estradiol were included in the study. Microdialysis was used to collect proteins from the extracellular space in vivo in 73 women; 12 with breast cancer, 42 healthy postmenopausal women with different breast densities, and 19 healthy premenopausal women. Breast density was determined as lean tissue fraction (LTF) using magnetic resonance imaging. Data were evaluated in a murine breast cancer model. We quantified a panel of 92 key proteins regulating metabolism using proximity extension assay. Results: We report that 29 proteins were upregulated in human breast cancer. In dense breasts 37 proteins were upregulated and 17 of these were similarly regulated as in breast cancer. 32 proteins correlated with LTF. In premenopausal breasts 19 proteins were up-regulated and 9 down-regulated. Of these, 27 correlated to estradiol, a result that was confirmed for most proteins in experimental breast cancer. Only two proteins, pro-cathepsin H and galanin peptide, were similarly regulated in breast cancer, dense- and estrogen exposed breasts. Conclusions: Metabolic proteins may be targetable for breast cancer prevention. Depending on risk factor, this may, however, require different approaches as breast density and estradiol induce distinct different expression patterns in the breast. Additionally, metabolic proteins from the extracellular space may indeed be further explored as therapeutic targets for breast cancer treatment.

Mathematical models for biomarker calculation of drug-induced liver injury in humans and experimental models based on gadoxetate enhanced magnetic resonance imaging.

BACKGROUND: Drug induced liver injury (DILI) is a major concern when developing new drugs. A promising biomarker for DILI is the hepatic uptake rate of the contrast agent gadoxetate. This rate can be estimated using a novel approach combining magnetic resonance imaging and mathematical modeling. However, previous work has used different mathematical models to describe liver function in humans or rats, and no comparative study has assessed which model is most optimal to use, or focused on possible translatability between the two species. AIMS: Our aim was therefore to do a comparison and assessment of models for DILI biomarker assessment, and to develop a conceptual basis for a translational framework between the species. METHODS AND RESULTS: We first established which of the available pharmacokinetic models to use by identifying the most simple and identifiable model that can describe data from both human and rats. We then developed an extension of this model for how to estimate the effects of a hepatotoxic drug in rats. Finally, we illustrated how such a framework could be useful for drug dosage selection, and how it potentially can be applied in personalized treatments designed to avoid DILI. CONCLUSION: Our analysis provides clear guidelines of which mathematical model to use for model-based assessment of biomarkers for liver function, and it also suggests a hypothetical path to a translational framework for DILI.

Fibromyalgia in women: association of inflammatory plasma proteins, muscle blood flow, and metabolism with body mass index and pain characteristics.

Introduction: Obesity is a common comorbidity in fibromyalgia (FM). Both FM and obesity have been connected to low-grade inflammation, although it is possible that previously reported inflammatory alterations in FM primarily may be linked to increased body mass index (BMI). Objective: This study aimed to investigate whether the inflammatory plasma protein profile, muscle blood flow, and metabolism and pain characteristics (clinical parameters and patient-reported outcome measurements) differed between female patients with FM with and without obesity. Methods: Patients with FM underwent clinical examinations, physical tests, and answered questionnaires. They were dichotomized according to BMI (<30 kg/m2 [n = 14]; ≥30 kg/m2 [n = 13]). Blood samples were collected and analyzed using a panel of 71 inflammatory plasma proteins. Results: There were significant (P < 0.05) differences in blood pressure, pulse, max VO2, pain intensity, physical capacity, and Fibromyalgia Impact Questionnaire between the groups; the obese group had higher blood pressure, pulse, pain intensity, and Fibromyalgia Impact Questionnaire. There were 14 proteins that contributed to the group belonging. The 4 most important proteins for the group discrimination were MIP1ß, MCP4, IL1RA, and IL6, which showed higher concentrations in obese patients with FM. Significantly decreased blood flow and increased concentration of pyruvate were detected in obese patients compared with nonobese patients. There was significant correlation between inflammatory proteins and sedentary behavior and health status in obese patients with FM. Conclusions: These findings suggest that metabolism and inflammation interact in female patients with FM with obesity and might cause chronic low-grade inflammation. Screening for obesity and monitoring of BMI changes should be considered in the treatment of patients with FM.

Digital twin predicting diet response before and after long-term fasting.

Today, there is great interest in diets proposing new combinations of macronutrient compositions and fasting schedules. Unfortunately, there is little consensus regarding the impact of these different diets, since available studies measure different sets of variables in different populations, thus only providing partial, non-connected insights. We lack an approach for integrating all such partial insights into a useful and interconnected big picture. Herein, we present such an integrating tool. The tool uses a novel mathematical model that describes mechanisms regulating diet response and fasting metabolic fluxes, both for organ-organ crosstalk, and inside the liver. The tool can mechanistically explain and integrate data from several clinical studies, and correctly predict new independent data, including data from a new study. Using this model, we can predict non-measured variables, e.g. hepatic glycogen and gluconeogenesis, in response to fasting and different diets. Furthermore, we exemplify how such metabolic responses can be successfully adapted to a specific individual's sex, weight, height, as well as to the individual's historical data on metabolite dynamics. This tool enables an offline digital twin technology.

Fibromyalgia: Associations Between Fat Infiltration, Physical Capacity, and Clinical Variables.

Background: Obesity is a risk factor for the development of fibromyalgia (FM) and generally most studies report increased Body Mass Index (BMI) in FM. Obesity in FM is associated with a worse clinical presentation. FM patients have low physical conditioning and obesity further exacerbates these aspects. Hitherto studies of FM have focused upon a surrogate for overall measure of fat content, ie, BMI. This study is motivated by that ectopic fat and adipose tissues are rarely investigated in FM including their relationships to physical capacity variables. Moreover, their relationships to clinical variables including are not known. Aims were to 1) compare body composition between FM and healthy controls and 2) investigate if significant associations exist between body composition and physical capacity aspects and important clinical variables. Methods: FM patients (n = 32) and healthy controls (CON; n = 30) underwent a clinical examination that included pressure pain thresholds and physical tests. They completed a health questionnaire and participated in whole-body magnetic resonance imaging (MRI) to determine body composition aspects. Results: Abdominal adipose tissues, muscle fat, and BMI were significantly higher in FM, whereas muscle volumes of quadriceps were smaller. Physical capacity variables correlated negatively with body composition variables in FM. Both body composition and physical capacity variables were significant regressors of group belonging; the physical capacity variables alone showed stronger relationships with group membership. A mix of body composition variables and physical capacity variables were significant regressors of pain intensity and impact in FM. Body composition variables were the strongest regressors of blood pressures, which were increased in FM. Conclusion: Obesity has a negative influence on FM symptomatology and increases the risk for other serious conditions. Hence, obesity, dietary habits, and physical activity should be considered when developing clinical management plans for patients with FM.

Breast density is strongly associated with multiparametric magnetic resonance imaging biomarkers and pro-tumorigenic proteins in situ.

BACKGROUND: High mammographic density is an independent risk factor for breast cancer by poorly understood molecular mechanisms. Women with dense breasts often undergo conventional magnetic resonance imaging (MRI) despite its limited specificity, which may be increased by diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) and contrast. How these modalities are affected by breast density per se and their association with the local microenvironment are undetermined. METHODS: Healthy postmenopausal women attending mammography screen with extremely dense or entirely fatty breasts underwent multiparametric MRI for analyses of lean tissue fraction (LTF), ADC and perfusion dynamics. Microdialysis was used for extracellular proteomics in situ. RESULTS: Significantly increased LTF and ADC and delayed perfusion were detected in dense breasts. In total, 270 proteins were quantified, whereof 124 related to inflammation, angiogenesis, and cellular growth were significantly upregulated in dense breasts. Most of these correlated significantly with LTF, ADC and the perfusion data. CONCLUSIONS: ADC and perfusion characteristics depend on breast density, which should be considered during the implementation of thresholds for malignant lesions. Dense and nondense breasts are two essentially different biological entities, with a pro-tumorigenic microenvironment in dense breasts. Our data reveal several novel pathways that may be explored for breast cancer prevention strategies.

Skeletal Myosteatosis is Associated with Systemic Inflammation and a Loss of Muscle Bioenergetics in Stable COPD.

Background: Common features among patients with more advanced chronic obstructive pulmonary disease (COPD) are systemic inflammation and a loss of both muscle mass and normal muscle composition. In the present study, we investigated COPD subjects to better understand how thigh muscle fat infiltration (MFI) and energy metabolism relate to each other and to clinical features of COPD with emphasis on systemic inflammation. Methods: Thirty-two Caucasians with stable COPD were investigated using questionnaires, lung function tests, blood analysis and magnetic resonance imaging (MRI) for analysis of body- and thigh muscle composition. Bioenergetics in the resting thigh muscle, expressed as the PCr/Pi ratio, were analysed using 31phosphorus magnetic resonance spectroscopy (31P-MRS). Results: Based on the combination of the MFI adjusted for sex (MFIa) and the thigh fat-tissue free muscle volume, expressed as the deviation from the expected muscle volume of a matched virtual control group (FFMVvcg), all COPD subjects displayed abnormally composed thigh muscles. Clinical features of increased COPD severity, including a decrease of blood oxygenation (r = -0.44, p < 0.05) and FEV1/FVC ratio, reflecting airway obstruction (r = -0.53, p < 0.01) and an increase of COPD symptoms (r = 0.37, p < 0.05) and breathing frequency at rest (r = 0.41, p < 0.05), were all associated with a raise of the PCr/Pi ratio in the thigh muscle. Increased MFIa of the thigh muscle correlated positively with markers of systemic inflammation (white blood cell count, r = 0.41, p < 0.05; fibrinogen, r = 0.44, p < 0.05), and negatively with weekly physical activity (r = -0.40, p < 0.05) and the PCr/Pi ratio in the resting thigh muscle (r = -0.41, p < 0.05). Conclusion: The present study implies a link between systemic inflammation, excessive MFI and a loss of bioenergetics in subjects with stable COPD.

Ectopic fat is associated with cardiac remodeling-A comprehensive assessment of regional fat depots in type 2 diabetes using multi-parametric MRI.

Background: Different regional depots of fat have distinct metabolic properties and may relate differently to adverse cardiac remodeling. We sought to quantify regional depots of body fat and to investigate their relationship to cardiac structure and function in Type 2 Diabetes (T2D) and controls. Methods: From the SCAPIS cohort in Linköping, Sweden, we recruited 92 subjects (35% female, mean age 59.5 ± 4.6 years): 46 with T2D and 46 matched controls. In addition to the core SCAPIS data collection, participants underwent a comprehensive magnetic resonance imaging examination at 1.5 T for assessment of left ventricular (LV) structure and function (end-diastolic volume, mass, concentricity, ejection fraction), as well as regional body composition (liver proton density fat fraction, visceral adipose tissue, abdominal subcutaneous adipose tissue, thigh muscle fat infiltration, fat tissue-free thigh muscle volume and epicardial adipose tissue). Results: Compared to the control group, the T2D group had increased: visceral adipose tissue volume index (P < 0.001), liver fat percentage (P < 0.001), thigh muscle fat infiltration percentage (P = 0.02), LV concentricity (P < 0.001) and LV E/e'-ratio (P < 0.001). In a multiple linear regression analysis, a negative association between liver fat percentage and LV mass (St Beta -0.23, P < 0.05) as well as LV end-diastolic volume (St Beta -0.27, P < 0.05) was found. Epicardial adipose tissue volume and abdominal subcutaneous adipose tissue volume index were the only parameters of fat associated with LV diastolic dysfunction (E/e'-ratio) (St Beta 0.24, P < 0.05; St Beta 0.34, P < 0.01, respectively). In a multivariate logistic regression analysis, only visceral adipose tissue volume index was significantly associated with T2D, with an odds ratio for T2D of 3.01 (95% CI 1.28-7.05, P < 0.05) per L/m2 increase in visceral adipose tissue volume. Conclusions: Ectopic fat is predominantly associated with cardiac remodeling, independently of type 2 diabetes. Intriguingly, liver fat appears to be related to LV structure independently of VAT, while epicardial fat is linked to impaired LV diastolic function. Visceral fat is associated with T2D independently of liver fat and abdominal subcutaneous adipose tissue.

Irritable bowel syndrome in women: Association between decreased insular subregion volumes and gastrointestinal symptoms.

OBJECTIVE: Irritable bowel syndrome (IBS) is a chronic pain disorder characterized by disturbed interactions between the gut and the brain with depression as a common comorbidity. In both IBS and depression, structural brain alterations of the insular cortices, key structures for pain processing and interoception, have been demonstrated but the specificity of these findings remains unclear. We compared the gray matter volume (GMV) of insular cortex (IC) subregions in IBS women and healthy controls (HC) and examined relations to gastrointestinal (GI) symptoms and glutamate + glutamine (Glx) concentrations. We further analyzed GMV of IC subregions in women with major depression (MDD) compared to HC and addressed possible differences between depression, IBS, IBS with depression and HC. DESIGN: Women with IBS (n = 75), MDD (n = 41) and their respective HC (n = 39 and n = 43) underwent structural brain MRI. IC subregion volumes were estimated using statistical parametric mapping software. General linear model approaches were applied to IC volumetric data and FDR-corrected partial correlation analyses assessed relations between GMV, GI symptoms and Glx concentrations. RESULTS: IBS patients had significantly smaller IC subregions than HC in both hemispheres but there was no significant difference between MDD compared with IBS and HC for any insular subregion. In IBS, the dorsal anterior insular volumes were negatively correlated with symptoms of nausea and pain, and the left ventral subregion showed a positive correlation with straining to defecate, while the posterior subregion volumes showed no relation to symptoms. In the anterior insula, concentration of Glx showed positive correlations with GMV bilaterally in HC and with GMV of the right anterior insula in IBS. CONCLUSION: As the interoceptive cortex, the insula shows substantial and disease-specific structural differences in patients with chronic interoceptive visceral pain. Particularly changes in the anterior proportions might be related to chronic exposure to or enhanced salience towards adverse interoceptive visceral signals and could be linked to biochemical changes, calling for further multimodal and longitudinal work.