Metabolic profiling of tryptophan pathways: Implications for obesity and metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: The rise in obesity highlights the need for improved therapeutic strategies, particularly in addressing metabolic dysfunction-associated steatotic liver disease (MASLD). We aim to assess the role of tryptophan metabolic pathways in the pathogenesis of obesity and in the different histological stages of MASLD. MATERIALS AND METHODS: We used ultra-high performance liquid chromatography to quantify circulating levels of 15 tryptophan-related metabolites from the kynurenine, indole and serotonin pathways. A cohort of 76 subjects was analysed, comprising 18 subjects with normal weight and 58 with morbid obesity, these last being subclassified into normal liver (NL), simple steatosis (SS) and metabolic dysfunction-associated steatohepatitis (MASH). Then, we conducted gene expression analysis of hepatic IDO-1 and kynyrenine-3-monooxygenase (KMO). RESULTS: Key findings in obesity revealed a distinct metabolic signature characterized by a higher concentration of different kynurenine-related metabolites, a decrease in indole-3-acetic acid and indole-3-propionic acid, and an alteration in the serotonin pathway. Elevated tryptophan levels were associated with MASLD presence (37.659 (32.577-39.823) µM of tryptophan in NL subjects; 41.522 (38.803-45.276) µM in patients with MASLD). Overall, pathway fluxes demonstrated an induction of tryptophan catabolism via the serotonin pathway in SS subjects and into the kynurenine pathway in MASH. We found decreased IDO-1 and KMO hepatic expression in NL compared to SS. CONCLUSIONS: We identified a distinctive metabolic signature in obesity marked by changes in tryptophan catabolic pathways, discernible through altered metabolite profiles. We observed stage-specific alterations in tryptophan catabolism fluxes in MASLD, highlighting the potential utility of targeting these pathways in therapeutic interventions.

Untargeted lipidomics analysis in women with morbid obesity and type 2 diabetes mellitus: A comprehensive study.

There is a phenotype of obese individuals termed metabolically healthy obese that present a reduced cardiometabolic risk. This phenotype offers a valuable model for investigating the mechanisms connecting obesity and metabolic alterations such as Type 2 Diabetes Mellitus (T2DM). Previously, in an untargeted metabolomics analysis in a cohort of morbidly obese women, we observed a different lipid metabolite pattern between metabolically healthy morbid obese individuals and those with associated T2DM. To validate these findings, we have performed a complementary study of lipidomics. In this study, we assessed a liquid chromatography coupled to a mass spectrometer untargeted lipidomic analysis on serum samples from 209 women, 73 normal-weight women (control group) and 136 morbid obese women. From those, 65 metabolically healthy morbid obese and 71 with associated T2DM. In this work, we find elevated levels of ceramides, sphingomyelins, diacyl and triacylglycerols, fatty acids, and phosphoethanolamines in morbid obese vs normal weight. Conversely, decreased levels of acylcarnitines, bile acids, lyso-phosphatidylcholines, phosphatidylcholines (PC), phosphatidylinositols, and phosphoethanolamine PE (O-38:4) were noted. Furthermore, comparing morbid obese women with T2DM vs metabolically healthy MO, a distinct lipid profile emerged, featuring increased levels of metabolites: deoxycholic acid, diacylglycerol DG (36:2), triacylglycerols, phosphatidylcholines, phosphoethanolamines, phosphatidylinositols, and lyso-phosphatidylinositol LPI (16:0). To conclude, analysing both comparatives, we observed decreased levels of deoxycholic acid, PC (34:3), and PE (O-38:4) in morbid obese women vs normal-weight. Conversely, we found elevated levels of these lipids in morbid obese women with T2DM vs metabolically healthy MO. These profiles of metabolites could be explored for the research as potential markers of metabolic risk of T2DM in morbid obese women.

Towards understanding post-COVID-19 condition: A systematic meta-analysis of transcriptomic alterations with sex-specific insights.

BACKGROUND: Post COVID-19 Condition (PCC), characterized by lingering symptoms post-acute COVID-19, poses clinical challenges, highlighting the need to understand its underlying molecular mechanisms. This meta-analysis aims to shed light on the transcriptomic landscapes and sex-specific molecular dynamics intrinsic to PCC. METHODS: A systematic review identified three studies suitable for comprehensive meta-analysis, encompassing 135 samples (57 PCC subjects and 78 recovered subjects). We performed meta-analysis on differential gene expression, a gene set enrichment analysis of Reactome pathways, and weighted gene co-expression network analysis (WGCNA). We performed a drug and disease enrichment analysis and also assessed sex-specific differences in expression patterns. KEY FINDINGS: A clear difference was observed in the transcriptomic profiles of PCC subjects, with 530 differentially expressed genes (DEGs) identified. Enrichment analysis revealed that the altered pathways were predominantly implicated in cell cycle processes, immune dysregulation and histone modifications. Antioxidant compounds such as hesperitin were predominantly linked to the hub genes of the DEGs. Sex-specific analyses highlighted disparities in DEGs and altered pathways in male and female PCC patients, revealing a difference in the expression of ribosomal proteins. PCC in men was mostly linked to neuro-cardiovascular disorders, while women exhibited more diverse disorders, with a high index of respiratory conditions. CONCLUSION: Our study reveals the intricate molecular processes underlying PCC, highlighting that the differences in molecular dynamics between males and females could be key to understanding and effectively managing the varied symptomatology of this condition.

Platelet-associated biomarkers in nonalcoholic steatohepatitis: Insights from a female cohort with obesity.

BACKGROUND: There is a lack of noninvasive diagnostic methods for nonalcoholic steatohepatitis (NASH), the severe condition of metabolic dysfunction-associated steatotic liver disease (MASLD). Platelet activation, evaluated through certain related parameters, is associated with liver disease and inflammation, but previous results are inconclusive. AIM: To investigate the potential utility of platelet-related indices as noninvasive diagnostic markers for the detection and prediction of MASLD, focusing on NASH. RESULTS: We found that mean platelet volume (MPV), plateletcrit (PCT) and platelet distribution width (PDW) were increased in the severe and morbidly obese (SMO) group compared to the normal weight (NW) group. We found decreased levels of MPV in steatosis and NASH patients. MPV and PCT values were decreased in the presence of mild liver inflammation. Platelet count (PLA) and PCT values were lower in the presence of ballooning. We obtained an area under the ROC curve of 0.84 using MPV and three other variables to predict MASLD. CONCLUSIONS: Some platelet-related indices vary depending on liver condition. Here, we reported decreased MPV in MASLD presence. Moreover, we presented for the first time a predictive model using MPV, ALT levels and the presence of diabetes mellitus and metabolic syndrome to predict MASLD in obese women. Also, MPV is closely related to early liver inflammation in NASH, and PLA and PCT are related to hepatic ballooning. These indices could be widely used for the early detection of NASH since they are usually determined in routine laboratory tests.

Clinical and Biomarker Profile Responses to Rehabilitation Treatment in Patients with Long COVID Characterized by Chronic Fatigue.

Long COVID (LC) syndrome is a complex multiorgan symptom that persists beyond >12 weeks after SARS-CoV-2 infection. The most frequently associated symptom is fatigue. Physical activity and exercise are recommended, although specific studies are lacking. The objectives of the present work are to analyze the impact of a supervised exercise program on the clinical evolution of LC with fatigue patients and to identify whether certain circulating biomarkers could predict the response to rehabilitation. The rehabilitation treatment response was analyzed in 14 women diagnosed with LC and fatigue, based on the changes in the 6 min walk test and Borg/Fatigue Impact scales. Patients who showed improvement in the meters walked were considered "responders" to the therapy. A total of 65% of patients responded to the exercise program, with an improvement in the meters walked and in oxygen saturation, with stability in the percentage of meters walked. Participants with obesity and those double-vaccinated against SARS-CoV-2 presented a lower degree of fatigue. LC patients presented a favorable response to a supervised exercise program. Differences in creatinine and protein levels were observed between rehabilitation therapy "responders" and "nonresponders". A good state of protein nutrition was related to a better rehabilitation response. The results are promising regarding possible predictive biomarkers of rehabilitation response, such as creatinine.

LC/MS-Based Untargeted Metabolomics Study in Women with Nonalcoholic Steatohepatitis Associated with Morbid Obesity.

This study investigated the importance of a metabolomic analysis in a complex disease such as nonalcoholic steatohepatitis (NASH) associated with obesity. Using an untargeted metabolomics technique, we studied blood metabolites in 216 morbidly obese women with liver histological diagnosis. A total of 172 patients were diagnosed with nonalcoholic fatty liver disease (NAFLD), and 44 were diagnosed with normal liver (NL). Patients with NAFLD were classified into simple steatosis (n = 66) and NASH (n = 106) categories. A comparative analysis of metabolites levels between NASH and NL demonstrated significant differences in lipid metabolites and derivatives, mainly from the phospholipid group. In NASH, there were increased levels of several phosphatidylinositols and phosphatidylethanolamines, as well as isolated metabolites such as diacylglycerol 34:1, lyso-phosphatidylethanolamine 20:3 and sphingomyelin 38:1. By contrast, there were decreased levels of acylcarnitines, sphingomyelins and linoleic acid. These findings may facilitate identification studies of the main pathogenic metabolic pathways related to NASH and may also have a possible applicability in a panel of metabolites to be used as biomarkers in future algorithms of the disease diagnosis and its follow-up. Further confirmatory studies in groups with different ages and sexes are necessary.

LC/MS-Based Untargeted Metabolomics Analysis in Women with Morbid Obesity and Associated Type 2 Diabetes Mellitus.

Obesity is a chronic and complex disease, with an increasing incidence worldwide that is associated with metabolic disorders such as type 2 diabetes mellitus (T2DM). Thus, it is important to determine the differences between metabolically healthy obese individuals and those with metabolic disorders. The aim of this study was to perform an untargeted metabolomics assay in women with morbid obesity (MO) compared to a normal weight group, and to differentiate the metabolome of these women with MO who present with T2DM. We carried out a liquid chromatography-mass spectrometry-based untargeted metabolomics assay using serum samples of 209 Caucasian women: 73 with normal weight and 136 with MO, of which 71 had T2DM. First, we found increased levels of choline and acylglycerols and lower levels of bile acids, steroids, ceramides, glycosphingolipids, lysophosphatidylcholines, and lysophosphatidylethanolamines in MO women than in the control group. Then, in MO women with T2DM, we found increased levels of glutamate, propionyl-carnitine, bile acids, ceramides, lysophosphatidylcholine 14:0, phosphatidylinositols and phosphoethanolamines, and lower levels of Phe-Ile/Leu. Thus, we found metabolites with opposite trends of concentration in the two metabolomic analyses. These metabolites could be considered possible new factors of study in the pathogenesis of MO and associated T2DM in women.

Expression of STING in Women with Morbid Obesity and Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disease. Although mostly benign, this disease can evolve into nonalcoholic steatohepatitis (NASH). The stimulator of interferon genes (STING) plays an important role in the immune response against stressed cells, but this protein may also be involved in liver lipogenesis and microbiota composition. In this study, the role of STING in NAFLD was evaluated by RT-qPCR to analyze STING mRNA abundance and by immunohistochemical analysis to evaluate protein expression in liver biopsies from a cohort composed of 69 women with morbid obesity classified according to their liver involvement (normal liver, n = 27; simple steatosis (SS), n = 26; NASH, n = 16). The results showed that STING mRNA expression in the liver increases with the occurrence of NAFLD, specifically in the SS stage in which the degree of steatosis is mild or moderate. Protein analysis corroborated these results. Positive correlations were observed among hepatic STING mRNA abundance and gamma-glutamyl transferase and alkaline phosphatase levels, hepatic Toll-like receptor 9 expression and some circulating microbiota-derived bile acids. In conclusion, STING may be involved in the outcome and progression of NAFLD and may be related to hepatic lipid metabolism. However, further studies are needed to confirm these findings.

The Role of Olfactomedin 2 in the Adipose Tissue-Liver Axis and Its Implication in Obesity-Associated Nonalcoholic Fatty Liver Disease.

This study's objective was to assess the involvement of olfactomedin 2 (OLFM2), a secreted glycoprotein related to lipid metabolism regulation, in nonalcoholic fatty liver disease (NAFLD) mediated by the adipose-tissue-liver axis. OLFM2 mRNA expression was analyzed in subcutaneous (SAT) and visceral (VAT) adipose tissue by RT-qPCR. The cohort included women with normal weight (n = 16) or morbid obesity (MO, n = 60) who were subclassified into normal liver (n = 20), simple steatosis (n = 21), and nonalcoholic steatohepatitis (NASH, n = 19) groups. The results showed that OLFM2 expression in SAT was enhanced in MO individuals and in the presence of NAFLD. Specifically, OLFM2 expression in SAT was increased in mild and moderate degrees of steatosis in comparison to the absence of it. Moreover, OLFM2 expression in SAT was negatively correlated with interleukin-6 levels. On the other hand, OLFM2 expression in VAT decreased in the presence of NASH and exhibited a positive correlation with adiponectin levels. In conclusion, OLFM2 in SAT seems to be implicated in hepatic lipid accumulation. Additionally, since we previously suggested the possible implication of hepatic OLFM2 in NAFLD progression, now we propose a possible interaction between the liver and SAT, reinforcing the potential implication of this tissue in NAFLD development.

Increased Hepatic ATG7 mRNA and ATG7 Protein Expression in Nonalcoholic Steatohepatitis Associated with Obesity.

The autophagy gene ATG7 has been shown to be essential for the induction of autophagy, a process that used to be suppressed in nonalcoholic fatty liver disease (NAFLD). However, the specific role of ATG7 in NAFLD remains unclear. The aim of this study was to analyze hepatic ATG7 mRNA and ATG7 protein expression regarding obesity-associated NAFLD. Patients included women classified into normal weight (NW, n = 6) and morbid obesity (MO, n = 72). The second group was subclassified into normal liver (NL, n = 11), simple steatosis (SS, n= 29), and nonalcoholic steatohepatitis (NASH, n = 32). mRNA expression was analyzed by RT-qPCR and protein expression was evaluated by Western blotting. Our results showed that NASH patients presented higher ATG7 mRNA and ATG7 protein levels. ATG7 mRNA expression was increased in NASH compared with SS, while ATG7 protein abundance was enhanced in NASH compared with NL. ATG7 mRNA correlated negatively with the expression of some hepatic lipid metabolism-related genes and positively with endocannabinoid receptors, adiponectin hepatic expression, and omentin levels. These results suggest that ATG7-mediated autophagy may play an important role in the pathogenesis of NAFLD, especially in NASH, perhaps playing a possible protective role. However, this is a preliminary study that needs to be further studied.

Circulating pyruvate is a potent prognostic marker for critical COVID-19 outcomes.

Background: Coronavirus-19 (COVID-19) disease is driven by an unchecked immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which alters host mitochondrial-associated mechanisms. Compromised mitochondrial health results in abnormal reprogramming of glucose metabolism, which can disrupt extracellular signalling. We hypothesized that examining mitochondrial energy-related signalling metabolites implicated in host immune response to SARS-CoV-2 infection would provide potential biomarkers for predicting the risk of severe COVID-19 illness. Methods: We used a semi-targeted serum metabolomics approach in 273 patients with different severity grades of COVID-19 recruited at the acute phase of the infection to determine the relative abundance of tricarboxylic acid (Krebs) cycle-related metabolites with known extracellular signaling properties (pyruvate, lactate, succinate and α-ketoglutarate). Abundance levels of energy-related metabolites were evaluated in a validation cohort (n=398) using quantitative fluorimetric assays. Results: Increased levels of four energy-related metabolites (pyruvate, lactate, a-ketoglutarate and succinate) were found in critically ill COVID-19 patients using semi-targeted and targeted approaches (p<0.05). The combined strategy proposed herein enabled us to establish that circulating pyruvate levels (p<0.001) together with body mass index (p=0.025), C-reactive protein (p=0.039), D-Dimer (p<0.001) and creatinine (p=0.043) levels, are independent predictors of critical COVID-19. Furthermore, classification and regression tree (CART) analysis provided a cut-off value of pyruvate in serum (24.54 µM; p<0.001) as an early criterion to accurately classify patients with critical outcomes. Conclusion: Our findings support the link between COVID-19 pathogenesis and immunometabolic dysregulation, and show that fluorometric quantification of circulating pyruvate is a cost-effective clinical decision support tool to improve patient stratification and prognosis prediction.

Are Ingested or Inhaled Microplastics Involved in Nonalcoholic Fatty Liver Disease?

Nonalcoholic fatty liver disease (NAFLD) has emerged as the predominant cause of chronic liver injury; however, the mechanisms underlying its progression have not been fully elucidated. Pathophysiological studies have stated that NAFLD is significantly influenced by dietary and environmental factors that could participate in the development of NAFLD through different mechanisms. Currently, "plastic pollution" is one of the most challenging environmental problems worldwide since several plastics have potential toxic or endocrine disputing properties. Specifically, the intake of microplastics (MPs) and nanoplastics (NPs) in water or diet and/or the inhalation from suspended particles is well established, and these particles have been found in human samples. Laboratory animals exposed to MPs develop inflammation, immunological responses, endocrine disruptions, and alterations in lipid and energy metabolism, among other disorders. MPs additives also demonstrated adverse reactions. There is evidence that MPs and their additives are potential "obesogens" and could participate in NAFLD pathogenesis by modifying gut microbiota composition or even worsen liver fibrosis. Although human exposure to MPs seems clear, their relationship with NAFLD requires further study, since its prevention could be a possible personalized therapeutic strategy. Adequate mitigation strategies worldwide, reducing environmental pollution and human exposure levels of MPs, could reduce the risk of NAFLD.

Increased Secreted Frizzled-Related Protein 5 mRNA Expression in the Adipose Tissue of Women with Nonalcoholic Fatty Liver Disease Associated with Obesity.

Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipocytokine secreted by adipocytes that seems to be linked with nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the role of the SFRP5-wingless-MMTV integration site family member 5a (WNT5A) pathway, closely related to adipogenesis, in subcutaneous (SAT) and visceral adipose tissues (VAT) and its relationship with obesity-related NAFLD. Our cohort was composed of 60 women with morbid obesity (MO), who underwent hypocaloric diet, subclassified according to their hepatic histopathology and 15 women with normal weight. We observed increased SFRP5 mRNA expression in VAT and lower WNT5A expression in SAT in MO compared to normal weight. We found elevated SFRP5 expression in nonalcoholic steatohepatitis (NASH) in SAT and in mild simple steatosis (SS) and NASH in VAT. We observed higher WNT5A expression in SS compared to normal liver in SAT, and a peak of WNT5A expression in mild SS. To conclude, we reported increased SFRP5 mRNA expression in SAT and VAT of NAFLD-related to obesity subjects, suggesting an implication of the SFRP5-WNT5A pathway in NAFLD pathogenesis, probably due to the adipose tissue-liver axis. Since the mechanisms by which this potential interaction takes place remain elusive, more research in this field is needed.

NASH Presence is Associated with a Lower Weight Loss One and 2 Years After Bariatric Surgery in Women with Severe Obesity.

PURPOSE: Given that obesity is a major medical problem associated with non-alcoholic fatty liver disease and the lack of studies on postsurgery weight loss according to hepatic histology, we aimed to analyse weight loss indicators according to non-alcoholic steatohepatitis (NASH) presence one and 2 years postsurgery. MATERIALS AND METHODS: The weight loss pattern of 410 women with severe obesity (SO) was analysed after sleeve gastrectomy (SG, n = 191) and Roux-en-Y gastric bypass (RYGB, n = 219) according to NASH presence at baseline and at 12 and 24 months postsurgery. Weight loss indicators: expected BMI (eBMI), excess BMI loss percentage (%EBMIL), total weight loss percentage (%TWL) and alterable weight loss percentage (%AWL). RESULTS: Unlike RYGB, after SG, a higher percentage of NASH patients do not reach the eBMI 2 years postsurgery. %TWL and %AWL presented no differences after RYGB despite the presence of NASH. After SG, there is a worse ponderal evolution of all indicators analysed in the presence of NASH. Unlike SG, diabetic patients lose less weight than non-diabetic patients after RYGB. The presence of NASH in diabetics had no impact on weight loss indicators, but in non-diabetics, it had an impact, particularly in the SG group. CONCLUSION: The presence of NASH suggests a worse weight loss pattern through all the analysed indicators one and 2 years after SG in women. The presence of T2DM appears to result in less weight loss after RYGB, but only non-diabetic women presenting NASH lose less weight that non-diabetic women in the absence of NASH after SG.

New Insights of OLFM2 and OLFM4 in Gut-Liver Axis and Their Potential Involvement in Nonalcoholic Fatty Liver Disease.

Olfactomedins (OLFMs) are a family of glycoproteins that play a relevant role in embryonic development and in some pathological processes. Although OLFM2 is involved in the regulation of the energy metabolism and OLFM4 is an important player in inflammation, innate immunity and cancer, the role of OLFMs in NAFLD-related intestinal dysbiosis remains unknown. In this study, we analysed the hepatic mRNA expression of OLFM2 and the jejunal expression of OLFM4 in a well-established cohort of women with morbid obesity (MO), classified according to their hepatic histology into normal liver (n = 27), simple steatosis (n = 26) and nonalcoholic steatohepatitis (NASH, n = 16). Our results showed that OLFM2 hepatic mRNA was higher in NASH, in advanced degrees of steatosis and in the presence of lobular inflammation. Additionally, we obtained positive correlations between hepatic OLFM2 and glucose, cholesterol, trimethylamine N-oxide and deoxycholic acid levels and hepatic fatty acid synthase, and negative associations with weight and jejunal Toll-like receptors (TLR4) and TLR5 expression. Regarding jejunal OLFM4, we observed positive correlations with circulating interleukin (IL)-8, IL-10, IL-17 and jejunal TLR9. In conclusion, OLFM2 in the liver seems to play a relevant role in NAFLD progression, while OLFM4 in the jejunum could be involved in gut dysbiosis-related inflammatory events.

Identification of the Potential Molecular Mechanisms Linking RUNX1 Activity with Nonalcoholic Fatty Liver Disease, by Means of Systems Biology.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disease; nevertheless, no definitive diagnostic method exists yet, apart from invasive liver biopsy, and nor is there a specific approved treatment. Runt-related transcription factor 1 (RUNX1) plays a major role in angiogenesis and inflammation; however, its link with NAFLD is unclear as controversial results have been reported. Thus, the objective of this work was to determine the proteins involved in the molecular mechanisms between RUNX1 and NAFLD, by means of systems biology. First, a mathematical model that simulates NAFLD pathophysiology was generated by analyzing Anaxomics databases and reviewing available scientific literature. Artificial neural networks established NAFLD pathophysiological processes functionally related to RUNX1: hepatic insulin resistance, lipotoxicity, and hepatic injury-liver fibrosis. Our study indicated that RUNX1 might have a high relationship with hepatic injury-liver fibrosis, and a medium relationship with lipotoxicity and insulin resistance motives. Additionally, we found five RUNX1-regulated proteins with a direct involvement in NAFLD motives, which were NFκB1, NFκB2, TNF, ADIPOQ, and IL-6. In conclusion, we suggested a relationship between RUNX1 and NAFLD since RUNX1 seems to regulate NAFLD molecular pathways, posing it as a potential therapeutic target of NAFLD, although more studies in this field are needed.

Resistin and IL-15 as Predictors of Invasive Mechanical Ventilation in COVID-19 Pneumonia Irrespective of the Presence of Obesity and Metabolic Syndrome.

The cytokine signature present in COVID-19 could provide information on the pathogenic mechanisms of the disease and could identify possible prognostic biomarkers and possible therapeutic targets. In this longitudinal work, we studied the clinical and biochemical parameters and circulating cytokine levels of 146 patients at the time of admission for COVID-19 and 4-6 weeks later. The main objective of this study was to determine whether basal cytokines could be early prognostic biomarkers of COVID-19, and also to analyze the impact of comorbidities, such as obesity or metabolic syndrome (MS), in the cytokine profile. The levels of most inflammatory cytokines were elevated on admission in relation to the level that was reached 4-6 weeks later, except for IL-1ß, which was lower on admission; these levels were irrespective of the presence of obesity or MS since the cytokine storm masks these inflammatory processes. Among the cytokines analyzed, those that correlated with a worse prognosis of COVID-19 were resistin, IL-6, IL-8, IL-15, MCP-1 and TNF-α. Specifically, resistin and IL-15 are the best early predictors of requiring invasive ventilation. Therefore, resistin and IL-15 should be included in the personalized treatment decision algorithm of patients with COVID-19.

Evolving mortality and clinical outcomes of hospitalized subjects during successive COVID-19 waves in Catalonia, Spain.

BACKGROUND: The changes in shield strategies, treatments, emergence variants, and healthcare pathways might shift the profile and outcome of patients hospitalized with COVID-19 in successive waves of the outbreak. METHODS: We retrospectively analysed the characteristics and in-hospital outcomes of all patients admitted with COVID-19 in eight university hospitals of Catalonia (North-East Spain) between Feb 28, 2020 and Feb 28, 2021. Using a 7-joinpoint regression analysis, we split admissions into four waves. The main hospital outcomes included 30-day mortality and admission to intensive care unit (ICU). FINDINGS: The analysis included 17,027 subjects admitted during the first wave (6800; 39.9%), summer wave (1807; 10.6%), second wave (3804; 22.3%), and third wave (4616; 27.1%). The highest 30-day mortality rate was reported during the first wave (17%) and decreased afterwards, remaining stable at 13% in the second and third waves (overall 30% reduction); the lowest mortality was reported during the summer wave (8%, 50% reduction). ICU admission became progressively more frequent during successive waves. In Cox regression analysis, the main factors contributing to differences in 30-day mortality were the epidemic wave, followed by gender, age, diabetes, chronic kidney disease, and neoplasms. INTERPRETATION: Although in-hospital COVID-19 mortality remains high, it decreased substantially after the first wave and is highly dependent of patient's characteristics and ICU availability. Highest mortality reductions occurred during a wave characterized by younger individuals, an increasingly frequent scenario as vaccination campaigns progress. FUNDING: This work did not receive specific funding.

Expression of Jejunal Taste Receptors in Women with Morbid Obesity.

Nutrient sensing plays important roles in promoting satiety and maintaining good homeostatic control. Taste receptors (TAS) are located through the gastrointestinal tract, and recent studies have shown they have a relationship with metabolic disorders. The aim of this study was to analyze the jejunal expression of TAS1R2, TAS1R3, TAS2R14 and TAS2R38 in women with morbid obesity, first classified according to metabolic syndrome presence (MetS; n = 24) or absence (non-MetS; n = 45) and then classified according to hepatic histology as normal liver (n = 28) or nonalcoholic fatty liver disease (n = 41). Regarding MetS, we found decreased expression of TAS2R14 in MetS patients. However, when we subclassified patients according to liver histology, we did not find differences between groups. We found negative correlations between glucose levels, triglycerides and MetS with TAS1R3 expression. Moreover, TAS2R14 jejunal expression correlated negatively with the presence of MetS and ghrelin levels and positively with the jejunal Toll-like receptor (TLR)4, peroxisome proliferator-activated receptor (PPAR)-γ, and interleukin (IL)-10 levels. Furthermore, TAS2R38 expression correlated negatively with TLR9 jejunal expression and IL-6 levels and positively with TLR4 levels. Our findings suggest that metabolic dysfunctions such as MetS trigger downregulation of the intestinal TASs. Therefore, taste receptors modulation could be a possible therapeutic target for metabolic disorders.