Identification of an alternative triglyceride biosynthesis pathway.

Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.

Autocrine FGF1 signaling promotes glucose uptake in adipocytes.

Fibroblast growth factor 1 (FGF1) is an autocrine growth factor released from adipose tissue during over-nutrition or fasting to feeding transition. While local actions underlie the majority of FGF1's anti-diabetic functions, the molecular mechanisms downstream of adipose FGF receptor signaling are unclear. We investigated the effects of FGF1 on glucose uptake and its underlying mechanism in murine 3T3-L1 adipocytes and in ex vivo adipose explants from mice. FGF1 increased glucose uptake in 3T3-L1 adipocytes and epididymal WAT (eWAT) and inguinal WAT (iWAT). Conversely, glucose uptake was reduced in eWAT and iWAT of FGF1 knockout mice. We show that FGF1 acutely increased adipocyte glucose uptake via activation of the insulin-sensitive glucose transporter GLUT4, involving dynamic crosstalk between the MEK1/2 and Akt signaling proteins. Prolonged exposure to FGF1 stimulated adipocyte glucose uptake by MEK1/2-dependent transcription of the basal glucose transporter GLUT1. We have thus identified an alternative pathway to stimulate glucose uptake in adipocytes, independent from insulin, which could open new avenues for treating patients with type 2 diabetes.

Elevated plasma bile acids coincide with cardiac stress and inflammation in young Cyp2c70-/- mice.

BACKGROUND: High plasma bile acids (BAs), for instance due to intrahepatic cholestasis of pregnancy or neonatal cholestasis, are associated with cardiac abnormalities. Here, we exploited the variability in plasma BA levels in Cyp2c70-/- mice with a human-like BA composition to investigate the acute effects of elevated circulating BAs on the heart. METHODS: RNA sequencing was performed on hearts of 3-week-old Cyp2c70-/- mice lacking mouse-specific BA species that show features of neonatal cholestasis. Cardiac transcriptomes were compared between wild-type pups, Cyp2c70-/- pups with low or high plasma BAs, and Cyp2c70-/- pups from dams that were perinatally treated with ursodeoxycholic acid (UDCA). RESULTS: We identified 1355 genes that were differentially expressed in hearts of Cyp2c70-/- mice with high versus low plasma BAs with enrichment of inflammatory processes. Strikingly, expression of 1053 (78%) of those genes was normalized in hearts of pups of UDCA-treated dams. Moreover, 645 cardiac genes strongly correlated to plasma BAs, of which 172 genes were associated with cardiovascular disease. CONCLUSIONS: Elevated plasma BAs alter gene expression profiles of hearts of mice with a human-like BA profile, revealing cardiac stress and inflammation. Our findings support the notion that high plasma BAs induce cardiac complications in early life. IMPACT: Cyp2c70-/- mice with a human-like bile acid composition show features of neonatal cholestasis but the extrahepatic consequences hereof have so far hardly been addressed Elevated plasma bile acids in Cyp2c70-/- pups coincide with cardiac stress and inflammation Perinatal treatment with UDCA prevents dysregulated cardiac gene expression patterns in Cyp2c70-/- pups.

Real-time quantification of laser speckle contrast imaging during intestinal laparoscopic surgery: successful demonstration in a porcine intestinal ischemia model.

BACKGROUND: Anastomotic leakage (AL) is a dreaded complication following colorectal cancer surgery, impacting patient outcome and leads to increasing healthcare consumption as well as economic burden. Bowel perfusion is a significant modifiable factor for anastomotic healing and thus crucial for reducing AL. AIMS: The study aimed to calculate a cut-off value for quantified laser speckle perfusion units (LSPUs) in order to differentiate between ischemic and well-perfused tissue and to assess inter-observer reliability. METHODS: LSCI was performed using a porcine ischemic small bowel loop model with the PerfusiX-Imaging® system. An ischemic area, a well-perfused area, and watershed areas, were selected based on the LSCI colormap. Subsequently, local capillary lactate (LCL) levels were measured. A logarithmic curve estimation tested the correlation between LSPU and LCL levels. A cut-off value for LSPU and lactate was calculated, based on anatomically ischemic and well-perfused tissue. Inter-observer variability analysis was performed with 10 observers. RESULTS: Directly after ligation of the mesenteric arteries, differences in LSPU values between ischemic and well-perfused tissue were significant (p < 0.001) and increased significantly throughout all following measurements. LCL levels were significantly different (p < 0.001) at both 60 and 120 min. Logarithmic curve estimation showed an R2 value of 0.56 between LSPU and LCL values. A LSPU cut-off value was determined at 69, with a sensitivity of 0.94 and specificity of 0.87. A LCL cut-off value of 3.8 mmol/L was found, with a sensitivity and specificity of 0.97 and 1.0, respectively. There was no difference in assessment between experienced and unexperienced observers. Cohen's Kappa values were moderate to good (0.52-0.66). CONCLUSION: Real-time quantification of LSPUs may be a feasible intraoperative method to assess tissue perfusion and a cut-off value could be determined with high sensitivity and specificity. Inter-observer variability was moderate to good, irrespective of prior experience with the technique.

Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70-/- mice with human-like bile acids.

BACKGROUND: Cyp2c70-/- mice with a human-like bile acid (BA) composition display features of neonatal cholestasis. We assessed whether perinatal ursodeoxycholic acid (UDCA) exposure prevents neonatal cholestasis in Cyp2c70-/- mice and reduces cholangiopathy development later in life. METHODS: Cyp2c70+/- males were crossed with Cyp2c70+/- females fed either a regular chow diet or a 0.1% UDCA-containing diet during breeding, gestation, and suckling. Cholestasis and liver function parameters were assessed in their Cyp2c70-/- and wild-type offspring at 3 and 8 weeks of age. RESULTS: Three-week-old Cyp2c70-/- pups showed features of neonatal cholestasis, including elevated plasma BAs and transaminases, which were completely prevented in Cyp2c70-/- pups upon perinatal UDCA exposure. In addition, UDCA administration to the dams corrected altered hepatic gene expression patterns in Cyp2c70-/- pups, reduced markers of fibrogenesis and inflammation, and prevented cholangiocyte proliferation. Yet, these beneficial effects of perinatal UDCA exposure were not retained into adulthood upon discontinuation of treatment. CONCLUSION: Perinatal exposure of Cyp2c70-/- mice to UDCA has beneficial effects on liver function parameters, supporting a direct role of BA hydrophobicity in the development of neonatal cholestasis in these mice. However, prevention of neonatal cholestasis in Cyp2c70-/- mice has no long-lasting effects on liver pathophysiology. IMPACT: This is the first study showing that perinatal UDCA exposure prevents features of neonatal cholestasis that are observed in mice with a human-like bile acid composition, i.e., Cyp2c70-/- mice. Perinatal UDCA exposure of Cyp2c70-/- pups leads to UDCA enrichment in their circulating bile acid pool and, consequently, to a reduced hydrophobicity of biliary bile acids. Perinatal UDCA exposure of Cyp2c70-/- pups has no long-lasting effects on the development of cholangiopathy after discontinuation of treatment. The results in this study expand current knowledge regarding acute and long-lasting effects of UDCA treatment in early life.

Diet quality, food intake and incident adult-onset asthma: a Lifelines Cohort Study.

PURPOSE: Dietary factors have been suggested as drivers of the rising prevalence of adult-onset asthma, but evidence is inconclusive, possibly due to the complex interrelation with obesity. We aim to explore the relation of diet quality and food intake with incident adult-onset asthma in normal weight and overweight adults of the prospective population-based Lifelines Cohort Study. METHODS: Incident adult-onset asthma was defined as self-reported asthma at ± 4-year follow-up, in adults free of airway disease at baseline. Diet quality scores and food group intake were assessed at baseline. Log-binomial regression analyses were used to estimate adjusted relative risks (RR) between dietary intake (per portion) and incident adult-onset asthma, in categories of BMI (cutoff: 25 kg/m2). RESULTS: 477 incident asthma cases (75% female, 62% overweight) and 34,698 controls (60% female, 53% overweight) were identified. Diet quality-assessed by the Lifelines Diet Score and Mediterranean Diet Score-was not associated with incident adult-onset asthma in the two BMI groups. Although the dietary intake of several food groups differed between cases and controls, after adjustment for confounders only few remained associated with adult-onset asthma, including red and processed meat (RR: 0.93 per 15 g intake; 95% CI 0.86-0.99) in the normal weight group and intake of cheese (RR 1.09 per 20 g intake; 95% CI 1.00-1.17) and vegetables (RR 1.10 per 50 g intake; 95% CI 1.00-1.21) in the overweight group. CONCLUSION: The results of this study question the role of food as a 'simple' predictor of adult-onset asthma and call for an integrative approach, including a range of modifiable lifestyle factors and further asthma phenotyping.

Intestinal Farnesoid X Receptor Modulates Duodenal Surface Area but Does Not Control Glucose Absorption in Mice.

Bile acids facilitate the intestinal absorption of dietary lipids and act as signalling molecules in the maintenance of metabolic homeostasis. Farnesoid X receptor (FXR) is a bile acid-responsive nuclear receptor involved in bile acid metabolism, as well as lipid and glucose homeostasis. Several studies have suggested a role of FXR in the control of genes regulating intestinal glucose handling. We applied a novel dual-label glucose kinetic approach in intestine-specific FXR-/- mice (iFXR-KO) to directly assess the role of intestinal FXR in glucose absorption. Although iFXR-KO mice showed decreased duodenal expression of hexokinase 1 (Hk1) under obesogenic conditions, the assessment of glucose fluxes in these mice did not show a role for intestinal FXR in glucose absorption. FXR activation with the specific agonist GS3972 induced Hk1, yet the glucose absorption rate remained unaffected. FXR activation increased the duodenal villus length in mice treated with GS3972, while stem cell proliferation remained unaffected. Accordingly, iFXR-KO mice on either chow, short or long-term HFD feeding displayed a shorter villus length in the duodenum compared to wild-type mice. These findings indicate that delayed glucose absorption reported in whole-body FXR-/- mice is not due to the absence of intestinal FXR. Yet, intestinal FXR does have a role in the small intestinal surface area.

Educating health care professionals on the importance of proper diets. An online course on nutrition, health, and sustainability.

The majority of university curricula for health professionals does not incorporate courses on human nutrition and its links with human and planetary health. This primarily applies to medical and pharmacy students, who have important counselling roles and are at the forefront of public health. To address this important issue, EIT Food recently launched an online course on nutrition, health, and sustainability. Learners were able to provide feedback on the course through an end-of-course survey and social interaction on the FutureLearn platform. The course was very well attended worldwide and received positive feedback from learners. A total of 3,858 students enrolled in the program, from >20 countries. Learners reported inadequate training on nutrition in their own curriculum and indicated they would use key insights from the course to inform their own practice. This report provides insights from the course, which could be used as guidance for future initiatives.

Altered bile acid kinetics contribute to postprandial hypoglycaemia after Roux-en-Y gastric bypass surgery.

BACKGROUND/OBJECTIVES: Bile acids (BA) act as detergents in intestinal fat absorption and as modulators of metabolic processes via activation of receptors such as FXR and TGR5. Elevated plasma BA as well as increased intestinal BA signalling to promote GLP-1 release have been implicated in beneficial health effects of Roux-en-Y gastric bypass surgery (RYGB). Whether BA also contribute to the postprandial hypoglycaemia that is frequently observed post-RYGB is unknown. METHODS: Plasma BA, fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), GLP-1, insulin and glucose levels were determined during 3.5 h mixed-meal tolerance tests (MMTT) in subjects after RYGB, either with (RYGB, n = 11) or without a functioning gallbladder due to cholecystectomy (RYGB-CC, n = 11). Basal values were compared to those of age, BMI and sex-matched obese controls without RYGB (n = 22). RESULTS: Fasting BA as well as FGF19 levels were elevated in RYGB and RYGB-CC subjects compared to non-bariatric controls, without significant differences between RYGB and RYGB-CC. Postprandial hypoglycaemia was observed in 8/11 RYGB-CC and only in 3/11 RYGB. Subjects who developed hypoglycaemia showed higher postprandial BA levels coinciding with augmented GLP-1 and insulin responses during the MMTT. The nadir of plasma glucose concentrations after meals showed a negative relationship with postprandial BA peaks. Plasma C4 was lower during MMTT in subjects experiencing hypoglycaemia, indicating lower hepatic BA synthesis. Computer simulations revealed that altered intestinal transit underlies the occurrence of exaggerated postprandial BA responses in hypoglycaemic subjects. CONCLUSION: Altered BA kinetics upon ingestion of a meal, as frequently observed in RYGB-CC subjects, appear to contribute to postprandial hypoglycaemia by stimulating intestinal GLP-1 release.

FXR overexpression alters adipose tissue architecture in mice and limits its storage capacity leading to metabolic derangements.

The bile acid-activated nuclear receptor, FXR (NR1H4), has been implicated in the control of lipid and energy metabolism, but its role in fat tissue, where it is moderately expressed, is not understood. In view of the recent development of FXR-targeting therapeutics for treatment of human metabolic diseases, understanding the tissue-specific actions of FXR is essential. Transgenic mice expressing human FXR in adipose tissue (aP2-hFXR mice) at three to five times higher levels than endogenous Fxr, i.e., much lower than its expression in liver and intestine, have markedly enlarged adipocytes and show extensive extracellular matrix remodeling. Ageing and exposure to obesogenic conditions revealed a strongly limited capacity for adipose expansion and development of fibrosis in adipose tissues of aP2-hFXR transgenic mice. This was associated with impaired lipid storage capacity, leading to elevated plasma free fatty acids and ectopic fat deposition in liver and muscle as well as whole-body insulin resistance. These studies establish that adipose FXR is a determinant of adipose tissue architecture and contributes to whole-body lipid homeostasis.

Potential of Intestine-Selective FXR Modulation for Treatment of Metabolic Disease.

Farnesoid X receptor controls bile acid metabolism, both in the liver and intestine. This potent nuclear receptor not only maintains homeostasis of its own ligands, i.e., bile acids, but also regulates glucose and lipid metabolism as well as the immune system. These findings have led to substantial interest for FXR as a therapeutic target and to the recent approval of an FXR agonist for treating primary biliary cholangitis as well as ongoing clinical trials for other liver diseases. Given that FXR biology is complex, including moderate expression in tissues outside of the enterohepatic circulation, temporal expression of isoforms, posttranscriptional modifications, and the existence of several other bile acid-responsive receptors such as TGR5, clinical application of FXR modulators warrants thorough understanding of its actions. Recent findings have demonstrated remarkable physiological effects of targeting FXR specifically in the intestine (iFXR), thereby avoiding systemic release of modulators. These include local effects such as improvement of intestinal barrier function and intestinal cholesterol turnover, as well as systemic effects such as improvements in glucose homeostasis, insulin sensitivity, and nonalcoholic fatty liver disease (NAFLD). Intriguingly, metabolic improvements have been observed with both an iFXR agonist that leads to production of enteric Fgf15 and increased energy expenditure in adipose tissues and antagonists by reducing systemic ceramide levels and hepatic glucose production. Here we review the recent findings on the role of intestinal FXR and its targeting in metabolic disease.

Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with obesity and type 2 diabetes. Currently, there is no approved pharmacological treatment for this disease, but improvement of insulin resistance using peroxisome proliferator-activated receptor-γ (PPARγ) agonists, such as thiazolidinediones (TZDs), has been shown to reduce steatosis and steatohepatitis effectively and to improve liver function in patients with obesity-related NAFLD. However, this approach is limited by adverse effects of TZDs. Recently, we have identified fibroblast growth factor 1 (FGF1) as a target of nuclear receptor PPARγ in visceral adipose tissue and as a critical factor in adipose remodeling. Because FGF1 is situated downstream of PPARγ, it is likely that therapeutic targeting of the FGF1 pathway will eliminate some of the serious adverse effects associated with TZDs. Here we show that pharmacological administration of recombinant FGF1 (rFGF1) effectively improves hepatic inflammation and damage in leptin-deficient ob/ob mice and in choline-deficient mice, two etiologically different models of NAFLD. Hepatic steatosis was effectively reduced only in ob/ob mice, suggesting that rFGF1 stimulates hepatic lipid catabolism. Potentially adverse effects such as fibrosis or proliferation were not observed in these models. Because the anti-inflammatory effects were observed in both the presence and absence of the antisteatotic effects, our findings further suggest that the anti-inflammatory property of rFGF1 is independent of its effect on lipid catabolism. Our current findings indicate that, in addition to its potent glucose-lowering and insulin-sensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD.

Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction.

BACKGROUND & AIMS: Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. Peroxisomes and mitochondria play key roles in various hepatic metabolic functions including lipid metabolism and energy production. To investigate the involvement of these organelles in the mechanisms underlying malnutrition-induced hepatic dysfunction we developed a rat model of malnutrition. METHODS: Weanling rats were placed on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Peroxisomal and mitochondrial structural features were characterized using immunofluorescence and electron microscopy. Mitochondrial function was assessed using high-resolution respirometry. A novel targeted quantitative proteomics method was applied to analyze 47 mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle and fatty acid ß-oxidation pathways. RESULTS: Low protein diet-fed rats developed hypoalbuminemia and hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated peroxisomal dysfunction. This was followed by changes in mitochondrial ultrastructure and increased mitochondrial content. Mitochondrial function was impaired due to multiple defects affecting respiratory chain complex I and IV, pyruvate uptake and several ß-oxidation enzymes, leading to strongly reduced hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial ß-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. CONCLUSIONS: Malnutrition leads to severe impairments in hepatic peroxisomal and mitochondrial function, and hepatic metabolic dysfunction. We discuss the potential future implications of our findings for the clinical management of malnourished children. LAY SUMMARY: Severe malnutrition in children is associated with metabolic disturbances that are poorly understood. In order to study this further, we developed a malnutrition animal model and found that severe malnutrition leads to an impaired function of liver mitochondria which are essential for energy production and a loss of peroxisomes, which are important for normal liver metabolic function.

A low-protein diet combined with low-dose endotoxin leads to changes in glucose homeostasis in weanling rats.

Severe malnutrition is a leading cause of global childhood mortality, and infection and hypoglycemia or hyperglycemia are commonly present. The etiology behind the changes in glucose homeostasis is poorly understood. Here, we generated an animal model of severe malnutrition with and without low-grade inflammation to investigate the effects on glucose homeostasis. Immediately after weaning, rats were fed diets containing 5 [low-protein diet (LP)] or 20% protein [control diet (CTRL)], with or without repeated low-dose intraperitoneal lipopolysaccharide (LPS; 2 mg/kg), to mimic inflammation resulting from infections. After 4 wk on the diets, hyperglycemic clamps or euglycemic hyperinsulinemic clamps were performed with infusion of [U-(13)C6]glucose and [2-(13)C]glycerol to assess insulin secretion, action, and hepatic glucose metabolism. In separate studies, pancreatic islets were isolated for further analyses of insulin secretion and islet morphometry. Glucose clearance was reduced significantly by LP feeding alone (16%) and by LP feeding with LPS administration (43.8%) compared with control during the hyperglycemic clamps. This was associated with a strongly reduced insulin secretion in LP-fed rats in vivo as well as ex vivo in islets but signficantly enhanced whole body insulin sensitivity. Gluconeogenesis rates were unaffected by LP feeding, but glycogenolysis was higher after LP feeding. A protein-deficient diet in young rats leads to a susceptibility to low-dose endotoxin-induced impairment in glucose clearance with a decrease in the islet insulin secretory pathway. A protein-deficient diet is associated with enhanced peripheral insulin sensitivity but impaired insulin-mediated suppression of hepatic glycogenolysis.

Protein and energy intake in intensive care unit survivors during the first year of recovery: A descriptive cohort study.

BACKGROUND: Many intensive care unit (ICU) survivors suffer long-term health issues that affect their quality of life. Nutrition inadequacy can limit their rehabilitation potential. This study investigates nutrition intake and support during ICU admission and recovery. METHODS: In this prospective cohort study, 81 adult ICU patients with stays ≥48 h were included. Data on dietary intake, feeding strategies, baseline and ICU characteristics, and 1-year outcomes (physical health and readmission rates) were collected. The number of patients achieving 1.2 gram per kilogram per day of protein and 25 kilocalories per kilogram per day at 3 months, 6 months, and 12 months after ICU admission was recorded. The impact of dietary supplementation during the year was assessed. Baseline characteristics, intake barriers, and rehabilitation's influence on nutrition intake at 12 months were evaluated, along with the effect of inadequate intake on outcomes. RESULTS: After 12 months, only 10% of 60 patients achieved 1.2 g/kg/day protein intake, whereas 28% reached the advised 25 kcal/kg/day energy target. Supplementary feeding significantly increased protein intake at 3, 6, and 12 months (P = 0.003, P = 0.012, and P = 0.033, respectively) and energy intake at 3 months (P = 0.003). A positive relation was found between female sex and energy intake at 12 months after ICU admission (ß = 4.145; P = 0.043) and taste issues were independently associated with higher protein intake (ß = 0.363; P = 0.036). However, achieving upper-quartile protein or energy intake did not translate into improved physical health outcomes. CONCLUSION: Continuous and improved nutrition care is urgently needed to support patients in reaching nutrition adequacy.

Development and validation of a Context-sensitive Positive Health Questionnaire (CPHQ): A factor analysis and multivariate regression study.

BACKGROUND: The concept of Positive Health (PH) has gained increasing attention as a way of measuring individuals' ability to adapt in the face of contextual challenges. However, a suitable measurement instrument for PH that encompasses contextual factors has not yet been developed. This paper responds to this need by developing a Context-specific Positive Health (CPH) measurement instrument that aligns with the Capability Approach (CA). METHODS: The measurement instrument was developed and tested among a representative sample of 1002 Dutch internet survey panel members with diverse sociodemographic backgrounds. The instrument was developed in two stages: a preparation phase consisting of focus groups and expert consultations, and a validation among a representative panel of Dutch citizens. The goal of the preparation phase, was to pilot test and refine previously proposed Positive Health questionnaires into an initial version of the CPHQ. The validation phase aimed to examine the initial CPHQ's factorial validity using Factor Analysis, and its concurrent validity using Multivariate Regression Analysis. RESULTS: The developed questionnaire demonstrated adequate factorial and concurrent validity. Furthermore, it explicitly includes an assessment of resilience, this being a key component of PH. CONCLUSIONS: The introduced measurement tool, the CPHQ, comprises 11 dimensions that we have labeled as follows: relaxation, autonomy, fitness, perceived environmental safety, exclusion, social support, financial resources, political representation, health literacy, resilience, and enjoyment. In this article, we present four major contributions. Firstly, we embedded the measurement in a theoretical framework. Secondly, we focused the questionnaire on a key concept of Positive Health - the "ability to adapt." Thirdly, we addressed issues of health inequality by considering contextual factors. Finally, we facilitated the development of more understandable measurement items.

Effect of dietary interventions on markers of type 2 inflammation in asthma: A systematic review.

INTRODUCTION: Type 2 (T2) inflammation is a key mechanism in the pathophysiology of asthma. Diet may have immunomodulatory effects, and a role for diet in T2 inflammation has been suggested in the literature. Indeed, diet and food allergies play a role in children with atopic asthma, but less is known about diet in relation to adult asthma, which is often non-atopic. OBJECTIVE: To review the effect of dietary interventions on markers of T2 inflammation in adults with asthma. METHODS: The databases PubMed, Embase, Cochrane Library, and CINAHL were searched for eligible studies until December 2022. We included studies of all types of foods, nutrients, diets or supplements, either as an exposure or as an intervention, in adults and adolescents with asthma. Outcomes of interest included the T2 biomarkers FeNO, eosinophils, IL-4, IL-5, IL-13, eosinophil cationic protein and eosinophil peroxidase. The methodological quality of eligible studies was systematically evaluated, and the results were summarised according to dietary clusters. RESULTS: The systematic search identified studies on the dietary clusters antioxidants (n = 14), fatty acids, (n = 14), Mediterranean-style diets (n = 5), phytotherapy (n = 7), prebiotics & probiotics (n = 8), vitamin D (n = 7), and other dietary factors (n = 5). Studies within the phytotherapy and omega-3 poly-unsaturated fatty acids (PUFA) clusters showed possible improvements in T2 inflammation. Furthermore, we found little evidence for an effect of antioxidants, prebiotics & probiotics, and Mediterranean-style diets on T2 inflammation. However, heterogeneity in study protocols, methodological shortcomings and limited power of almost all studies make it difficult to fully determine the impact of different dietary approaches on T2 inflammation in asthma. CONCLUSIONS: Overall, the current evidence does not support a specific dietary intervention to improve T2 inflammation in asthma. Interventions involving phytotherapy and omega-3 PUFA currently have the best evidence and warrant further evaluation in well-designed and adequately powered studies, while taking into account T2-high phenotypes of asthma.

Muscle Function in Moderate to Severe Asthma: Association With Clinical Outcomes and Inflammatory Markers.

BACKGROUND: Patients with severe asthma have been shown to have low muscle mass, but the clinical consequences are unknown. OBJECTIVE: In a clinical cohort of patients with moderate to severe asthma, we aimed to assess muscle mass and strength and their relation with functional and clinical outcomes, as well as with systemic inflammatory markers. METHODS: Muscle mass and strength were assessed by the fat-free mass index (FFMI), creatinine excretion in a 24-hour urine sample, and handgrip strength test. Functional outcomes included pulmonary function tests and the 6-minute walking distance, whereas clinical outcomes were assessed with questionnaires on asthma control, quality of life, and health care use. Associations of muscle mass and strength with asthma outcomes were assessed with multivariable regression analyses. RESULTS: A total of 114 patients participated (36% male; mean age, 51.9 ± 14.4 years; body mass index, 27.7 ± 5.7 kg/m2). According to predefined criteria, 16% had a low FFMI and 8% a low urinary creatinine excretion, which did not differ between categories of asthma severity. Both lower FFMI and urinary creatinine excretion were associated with lower values of FEV1 and 6-minute walking distance, whereas a lower handgrip strength was related to worse asthma control, poorer quality of life, and a higher probability of emergency visits (all P < .05). Except for higher leukocytes in relation to lower FFMI, we did not find associations between systemic inflammatory markers and muscle function. CONCLUSIONS: This study demonstrates that low muscle mass is prevalent in patients with moderate to severe asthma and, along with low muscle strength, is associated with poorer clinical and functional outcomes. Our results encourage longitudinal studies into muscle function as a potential target for treatment to improve asthma outcomes.

Dietary Inflammatory Index and Clinical Outcome Measures in Adults With Moderate-to-Severe Asthma.

BACKGROUND: Diet is increasingly recognized as a modifiable factor in lung health, predominantly due to the immunomodulatory effects of nutrients. The Dietary Inflammatory Index (DII) is a score developed to express the inflammatory potential of a diet. OBJECTIVE: We aimed to assess the association of the DII and food groups, with clinical, functional, and inflammatory asthma outcomes in adults with asthma. METHODS: Patients with moderate-to-severe asthma were included in this cross-sectional study between June 2019 and October 2021, and completed a 3-day food diary, to calculate the DII and intake of food groups (ie, fruits, whole grains, processed meats, and sugar-sweetened beverages). Functional outcomes included pulmonary function tests and the 6-minute walking distance, whereas clinical outcomes were assessed using questionnaires on asthma control, quality of life, and health care utilization. Inflammatory markers were exhaled nitric oxide and blood leukocytes, eosinophils, and IL-6. Multivariable regression analyses were used to examine the association of DII and food groups with asthma outcomes. RESULTS: A total of 109 patients participated (35% male, mean ± standard deviation age 51.8 ± 14.2 years, body mass index 27.4 ± 5.3 kg/m2). Overall, 62% had a DII score >0, indicating a proinflammatory diet, which was not related to asthma severity. A more proinflammatory diet was consistently associated with lower forced vital capacity (%pred), but inconsistent results were observed with respect to airway obstruction. Neither the DII nor food groups were associated with clinical outcomes. Except for higher levels of exhaled nitric oxide in relation to an anti-inflammatory diet, we found no associations between inflammatory markers and the DII. CONCLUSION: Results from this cross-sectional study among patients with moderate-to-severe asthma do not support the hypothesis that a proinflammatory diet is associated with worse asthma outcomes, although limitations in study design and dietary intake estimation should be considered. Future well-designed experimental studies are needed to assess whether targeting the inflammatory potential of diet could lead to better outcomes in adults with asthma.

The prevalence of mental frailty in ICU survivors and informal caregiver strain: A 1-year retrospective study of the Frisian aftercare cohort.

Background: Intensive care unit (ICU) survivors often suffer from long-term mental problems and a reduced health-related quality of life (HRQoL). Symptoms of depression, anxiety, and post-traumatic stress disorder may render patients mentally frail post-ICU, resulting in impaired recovery and an increased informal caregiver burden. The aim of this study was to investigate the prevalence of mental frailty up to 12 months after ICU admission and pinpoint markers for early risk-assessment in clinical practice. Methods: A retrospective cohort study (2012-2018) in which clinical and post-ICU data of long-stay (⩾48 h) ICU-patients was used. Mental frailty was identified as clinically relevant symptoms of depression, anxiety, or post-traumatic distress disorder at 12 months after discharge. Results: The prevalence of mental frailty at 12 months post-ICU among the total group of 239 patients was 38%. Mental frailty was defined as clinically relevant symptoms of depression, anxiety, and/or trauma. To achieve this, previously validated cut off values were used for the HADS (HADS-Anxiety ⩾ 8; HADS-Depression ⩾ 8) and TSQ (⩾6), and CSI (⩾7). Conclusion: A significant proportion of ICU-survivors can be identified as mentally frail, which is associated with impaired HRQoL at baseline and post-ICU, and high caregiver strain. These findings emphasize the need for integrative aftercare programs for both the patient and their informal caregivers.