Metabolic Parameters Research Articles

Multi-target Phenylpropanoids Against Epilepsy.

Epilepsy is a neurological disease with no defined cause, characterized by recurrent epileptic seizures. These occur due to the dysregulation of excitatory and inhibitory neurotransmitters in the central nervous system (CNS). Psychopharmaceuticals have undesirable side effects; many patients require more than one pharmacotherapy to control crises. With this in mind, this work emphasizes the discovery of new substances from natural products that can combat epileptic seizures. Using in silico techniques, this review aims to evaluate the antiepileptic and multi-target activity of phenylpropanoid derivatives. Initially, ligand-based virtual screening models (LBVS) were performed with 468 phenylpropanoid compounds to predict biological activities. The LBVS were developed for the targets alpha- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), voltage-gated calcium channel Ttype (CaV), gamma-aminobutyric acid A (GABAA), gamma-aminobutyric acid transporter type 1 (GAT-1), voltage-gated potassium channel of the Q family (KCNQ), voltage-gated sodium channel (NaV), and N-methyl D-aspartate (NMDA). The compounds that had good results in the LBVS were analyzed for the absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and later, the best molecules were evaluated in the molecular docking consensus. The TR430 compound showed the best results in pharmacokinetic parameters; its oral absorption was 99.03%, it did not violate any Lipinski rule, it showed good bioavailability, and no cytotoxicity was observed either from the molecule or from the metabolites in the evaluated parameters. TR430 was able to bind with GABAA (activation) and AMPA (inhibition) targets and demonstrated good binding energy and significant interactions with both targets. The studied compound showed to be a promising molecule with a possible multi-target activity in both fundamental pharmacological targets for the treatment of epilepsy.

Glucose Metabolism and Sex Hormones in Male Patients with Medication-naïve First-episode Schizophrenia: A Large-scale Cross-sectional Study.

Schizophrenia (SCZ) usually begins in early adult life. The underlying molecular mechanisms of SCZ remain unclear. There is evidence for the involvement of abnormalities in metabolic and endocrine systems in SCZ, even in drug-naïve first-episode schizophrenia patients (DNFES). However, the association between impaired regulation of glucose metabolism and sex hormones was not studied in SCZ. This study aimed to evaluate the interrelationship between sex hormones and high fasting glucose levels in male DNFES patients. A total of 99 patients with SCZ were recruited, and fasting glucose, fasting insulin, the insulin resistance index (HOMA-IR), and sex hormones were measured. We found that some male patients with SCZ had abnormal levels in glucose metabolism parameters and gonadal hormones that were not within the normal range. Linear regression analysis adjusted for age, waist circumference, and body mass index showed that testosterone levels were negatively associated with fasting insulin in male patients (β = -0.21, t = -2.2, p = 0.03). Our findings confirm the abnormalities in glucose metabolism parameters and gonadal hormones at the onset of the illness in male DNFES patients with SCZ. In addition, there was an interaction effect between abnormal glucose metabolism and sex hormones in male patients.

Cardiovascular Safety of Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in Virologically Suppressed PLWHIV: A Comparative Analysis of CVD Scores.

The Aim of this study is to assess the cardiovascular safety of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF). We analyzed data from 37 virologically suppressed people living with HIV starting DOR/3TC/TDF, collecting viro-immunological and metabolic parameters as well as the 10-year risk of cardiovascular disease (10Y-CD) using both the Framingham risk score and D:A:D score.After 48 weeks, we observed a significant reduction in 10Y-CD both via the Framingham score (-0.7, p = .021) and the D:A:D score (-0.41, p = .012). After 96 weeks, we registered a significant reduction in 10Y-CD calculated via the D:A:D score (-0.98, p = .009). Regarding serum lipid markers, after 48 weeks we observed a significant reduction in total cholesterol (-17 mg/dL, p < .001), triglycerides (-21 mg/dL, p = .015), and LDL cholesterol (-8 mg/dL, p = .022). After 96 weeks, we registered a significant reduction in total cholesterol (-19 mg/dL, p < .001). DOR/3TC/TDF has shown a favorable metabolic profile, with a significant reduction in 10Y-CD, independently from the use of lipid-lowering drugs.

Signature of diabetic cardiomyopathy progression using high-fat diet and streptozotocin mouse model: from subclinical to clinical with three-hit mouse model

Abstract Background Diabetic cardiomyopathy (DbCM) is a pre-heart failure (pre-HF) condition that usually exhibits early diastolic dysfunction and evolving systolic dysfunction, along with left ventricular (LV) remodelling. Although DbCM shows distinct pathophysiology, the transition from the subclinical to the symptomatic stage is not straightforward and usually involves multifaceted processes which are not fully understood. Purpose To define the signature of DbCM progression in a novel mouse model using longitudinal echocardiography and multi-omics approaches. Methods Male mice (C57BL/6) were fed with high-fat diet (HFD) or control diet (CD) for 24 weeks, with single dose of streptozotocin (STZ) or vehicle injection at 8 weeks (n=10 each). Serial functional and metabolic parameters were measured prior to endpoint single nuclei RNA sequencing (snRNA-seq) and mass spectrometry-based proteomics analysis with comparison to cardiac remodelling to define detailed mechanisms underlying DbCM progression. Results HFD/STZ mice developed type 2 diabetes mellitus (T2DM) based on higher fasting blood glucose and HbA1C levels, insulin resistance and decreased beta-cell function (HOMA-IR and HOMA-beta, respectively) compared to controls. Progressive diastolic dysfunction was evident in HFD/STZ mice compared to CD mice based on enlarged LVPW;d from 12 weeks (P&amp;lt;0.05), reduced MV E/A ratio (P&amp;lt;0.01) and IVRT (P&amp;lt;0.05) from 16 weeks, and increased cardiac filling pressure (Left atrial (LA) area and LA volume) at 24 weeks, with preserved systolic function. This was paralleled by elevated collagen deposition (Picrosirius red), myocyte cross-sectional area and Col1a1 expression in HFD/STZ versus CD mice (all P&amp;lt;0.05). snRNA-seq analysis indicated preferential monocyte migration into diabetic hearts (P&amp;lt;0.01) whilst inflammatory pathways were activated across all cardiac cell types. Proteomics analysis revealed elevated expression of the established inflammation marker, plasma C-reactive protein (CRP), in HFD/STZ versus CD mice (P&amp;lt;0.05), which was correlated with worsening diastolic function (MV E/A ratio: r=-0.839, P&amp;lt;0.01) and LV hypertrophy (LVPW;d: r=0.861, P&amp;lt;0.01). Conclusion Our HFD/STZ mouse model offers a ‘three-hit’ approach which effectively captures key stages of clinical DbCM progression: 1) T2DM with insulin resistance, 2) progressive diastolic dysfunction with elevated chronic filling pressure and cardiac remodelling, and 3) systemic inflammation. This improved HFD/STZ mouse model is therefore appropriate to support a detailed study of mechanisms underlying DbCM progression and subsequent translation.

The effect of different dietary restriction on weight management and metabolic parameters in people with type 2 diabetes mellitus: a network meta-analysis of randomized controlled trials

The effect of different dietary restriction on weight management and metabolic parameters in people with type 2 diabetes mellitus: a network meta-analysis of randomized controlled trials

Cumulative effect of lifetime smoking history on arterial stiffness and subclinical atherosclerosis in patients with arterial hypertension

Abstract Introduction Although the effect of smoking status on blood pressure (BP) changes is well known an adverse association between cumulative smoke exposure (by pack-years) and functional and structural changes in arteries of patients with high BP has not been consistently demonstrated. Aim of the study was to explore the contributions of cumulative smoke exposure to the vascular consequences of arterial hypertension. Methods Indices of vascular function and structure including carotid-femoral pulse wave velocity (PWV), augmentation index (AIx) and carotid intima media thickness (cIMT) were measured in 485 adults aged less than 60 years old without a history of cardiovascular disease. The cohort was divided into three groups according to office systolic BP (SBP) and diastolic BP (DBP): normal (SBP &amp;lt;130 and DBP &amp;lt;85 mmHg, n=242), high normal (130≤SBP&amp;lt;140 or DBP 85≤DBP&amp;lt;90mmHg, n=96), and hypertension (SBP≥140 or DBP≥90mmHg, n=147). The cohort was subdivided according to pack-years of smoking history as never smokers (0.0 pack-years), light smokers (&amp;lt;20 pack-years), moderate smokers (20-40 pack-years), and heavy smokers (&amp;gt; 40 pack-years). Results The three BP groups had similar age and metabolic parameters (body mass index, fasting blood glucose and LDL-C). Figure shows PWV, AIx and carotid IMT by smoking exposure, stratified by BP level. The lowest PWV level was observed in never smokers with normal BP; whereas heavy smokers with hypertension exhibited the highest PWV. Also of note, heavy smokers with normal BP exhibited comparable PWV to light and never smokers with hypertension. Furthermore, in smokers with more than 20 pack-years tobacco exposure, PWV was higher among patients with high normal BP compared to subjects with normal BP (all P&amp;lt;0.01). In contrast to the monotonic increases in PWV and AIx by BP and pack-years smoking history, carotid IMT was generally similar among BP groups on the basis of cumulative exposure category. This finding may indicate a plateau in subclinical atherosclerotic burden over cumulative tobacco exposure for all BP categories. Conclusion Tobacco cumulative exposure adversely modify the effect of BP on arterial stiffness. Given that most adults who smoke start before the age 18 years, efforts to promote smoking cessation should continue to target younger adults with high BP.BP, tobacco exposure-vascular changes

Effects of SGLT-2i and GLP-1RA in vascular function parameters: the impact of the weight loss

Abstract Background Arterial stiffness and endothelial function markers flag increased cardiovascular disease risk in patients with type 2 Diabetes Mellitus (T2DM), while weight management plays a crucial role for the management of glycemic control and prevention of complications in these patients. Purpose To investigate the effects of novel antidiabetic agents on arterial stiffness and endothelial function as well as the metabolic parameters of HbA1c and Weight in T2DM patients. Patients and Methods: We enrolled 99 consecutive patients under stable antidiabetic therapy who did not reach therapeutic targets. Subjects were assessed to receive an additional antidiabetic agent to optimize glucose control; glucagon like peptide-1 receptor agonist (GLP-1RA, n=50) or sodium/glucose cotransporter-2 inhibitor (SGLT-2i, n=49). Glycosylated hemoglobin (Hba1c) and weight expressed through Body Mass Index (BMI) along with carotid-femoral pulse wave velocity (PWV) and flow-mediated dilatation (FMD), as biomarkers of arterial stiffness and endothelial function accordingly, were measured at baseline and 3 months after treatment intensification. Results There were no differences between the study groups in traditional risk factors of age and sex or baseline HbA1c, BMI, PWV, and FMD levels (ps=NS for all). In both groups PWV values displayed a statistically significant improvement from 11.2±2.5 to 9.3±2.2 m/sec (p&amp;lt;0.001) in the GLP-1RA group and from 10.7±2.4 to 8.9±2.0 m/sec (p=0.001) in the SGLT-2i group, as presented in Figure 1 through the differences in the values of PWV. FMD values were also significantly improve in both groups from baseline to follow-up; from 6.04±1.22 to 6.50±1.26% (p&amp;lt;0,001) for the GLP-1RA group and from 6.38±1.21 to 6.81±1.29% (p&amp;lt;0.001) for the SGLT-2i group. Moreover, both groups achieved better weight management goals in terms of BMI values between baseline and follow-up; from 33.6±4.9 to 31.5±4.6 kg/m2 for the GLP-1RA group (p&amp;lt;0.001) and from 31.8±5.5 to 30.5±5.6 kg/m2 for the SGLT-2i group (p&amp;lt;0.001), in addition to achieving better glycemic control in terms of HbA1c values, as seen in their paired differences: for GLP-1RA: 1.3±0.7% and for SGLT-2i: 0.8±0.5%. Interestingly, in the SGLT-2i group the magnitude of the PWV improvement was correlated with the weight loss (r=0.368, p=0.007). Conclusion These data provide evidence that the newer antidiabetic drugs, both GLP1-RA and SGLT-2i, have actions that benefit both vascular function, endothelium as well as metabolic parameters. Interestingly, in the patients receiving SGLT-2i the magnitude of the PWV improvement was correlated with the weight loss.delta PWV for SGLT-2i &amp; GLP-1RA groupsCorrelation of deltaWeight &amp; deltaPWV

Water deprivation induces a systemic pro-catabolic state that differentially affects oxidative and glycolytic skeletal muscles in male mice.

Dehydration, characterized by the loss of total body water and/or electrolytes due to diseases or inadequate fluid intake, is prevalent globally but often underestimated. Its contribution to long-term chronic diseases and sarcopenia is recognized, yet the mechanisms involved in systemic and muscle protein metabolism during dehydration remain unclear. This study investigated metabolic adaptations in a 36-hour water deprivation (WD) model of mice. Male C57BL/6 mice underwent 36-h WD or pair-feeding at rest, with assessments of motor skills along with biochemical, and metabolic parameters. Dehydration was confirmed by hypernatremia, body mass loss, hyporexia, and increased activity of vasopressinergic and oxytocinergic neurons compared to controls. These results were associated with liver mass loss, decreased glycaemia, and increased cholesterolemia. Additionally, increased VO2 and a decreased respiratory exchange ratio indicated reduced carbohydrate consumption and potentially increased protein use during dehydration. Thus, skeletal muscle protein metabolism was evaluated due to its high protein content. In the oxidative muscles of the WD group, total and proteasomal proteolysis increased, which was associated with decreased Akt-mediated intracellular signaling. Interestingly, there was an increase in fiber cross-sectional area, likely due to higher muscle water content caused by increased intracellular osmolality induced by protein catabolism products. Conversely, no changes were observed in protein turnover or water content in glycolytic muscles. These findings suggest that short-term WD imposes a pro-catabolic state, depleting protein content in skeletal muscle. However, skeletal muscle may respond differently to dehydration based on its phenotype and might adapt for a limited time.

LCoRL regulates growth and metabolism.

Genome Wide Association Studies (GWAS) in humans and livestock have identified genes associated with metabolic traits. However, the causality of many of these genes on metabolic homeostasis is largely unclear due to lack of detailed functional analyses. Here we report Ligand Dependent Corepressor-Like (LCoRL) as a metabolic regulator for body weight and glucose homeostasis. Although GWAS data show that LCoRL is strongly associated with body size, glucose homeostasis, and other metabolic traits in humans and livestock, functional investigations had not been performed. We generated Lcorl knockout mice (Lcorl-/-) and characterized the metabolic traits. We found that Lcorl-/- pups are born smaller than the wildtype littermates (WT) before reaching normal weight by 7-9 weeks of age. While aging, Lcorl-/- mice remain lean compared to WT mice, which is associated with a decrease in daily food intake. Glucose tolerance and insulin sensitivity are improved in Lcorl-/- mice. Mechanistically, this stunted growth is linked to a reduction of circulating levels of insulin like growth factor-1. The expression of the genes downstream of growth hormone signaling and the genes involved in glucose and lipid metabolism are altered in the liver of Lcorl-/- mice. Furthermore, Lcorl-/- mice are protected against a high-fat diet (HFD) challenge and show reduced exercise capacity in an exercise stress test. Collectively, our results are congruent with many of the metabolic parameters linked to the Lcorl locus as reported in GWAS in humans and livestock.

Genetic predisposition of metabolic syndrome independent of weight in premature atherosclerosis

Abstract Background Family history is a significant predictor of premature atherosclerotic cardiovascular events, which suggest that a genetic susceptibility underlies the development of premature atherosclerosis. Rather than the influence of single classic risk factors, such as hypertension, diabetes and dyslipidemia, these risk factors could be part of an underlying genetic insulin resistance or metabolic syndrome Methods Data on patients and their first degree family members visiting premature atherosclerosis clinic in a university medical centre, from 2007 until 2023 was analyzed. We divided them in controls (CACs=0 and Age &amp;gt;40 years), subclinical ASCVD (sASCVD) (CAC score ≥80th percentile) and premature ASCVD (PAS). We used principal component analysis (PCA) for clustering the predictor variables and generalized linear mixed model (GLMM) to analyze the mutual relationship between different clusters. The model performance was further validated in predicting the premature ASCVD. Result There were 1551 individuals divided across control (n=438), sASCVD (n=309) and PAS (804). We found 12 variables univariate significantly related to sASCVD. Using a principal component analysis (PCA) approach, these variables were loaded across 4 clusters which were defined as 1. Metabolic (elevated glucose or diabetes, elevated blood pressure or Hypertension, elevated Triglycerides, elevated waist circumference and elevated LDL-C); 2. Liver (elevated ALAT, elevated GGT, elevated triglycerides, decreased thrombocytes) 3. Inflammatory (decreased HDL-C, elevated Triglycerides and elevated leucocyte count) and 4. Lipid (elevated Lp(a) and elevated LDL-C). After mutual correction and model building, the metabolic (OR; 95% CI) (1.82; 1.48-2.27) and Liver clusters (1.20; 1.00-1.45) were only found to be significantly associated with risk of sASCVD. However, we did not find any association of inflammatory (1.19; 0.98-1.44) and lipid cluster (1.19; 0.99-1.41) with risk of sASCVD. Besides, association of these clusters with risk of sASCVD significantly varies among families suggested from variance of intercept when family was kept as a random effect in GLMM model and no interaction was noticed with BMI. We checked the performance of this model on premature atherosclerosis cohort and found model had a good discriminatory (AUC, 0.762; 0.735-0.790; P=0.001) ability for predicting PAS [Figure 1]. Conclusion In conclusion, our findings are suggestive of a significant association between metabolic syndrome factors and an increased risk of sASCVD in individuals with family history of premature atherosclerosis, regardless of weight. This association suggests the potential genetic predisposition towards premature atherosclerosis driving the observed metabolic parameters clustering in these individuals. Besides, the model demonstrated robust discriminatory power to predict premature atherosclerosis.ROC curve for premature atherosclerosis

Statins have profound effects on the epicardial fat transcriptome

Abstract Background Epicardial adipose tissue (EAT) has direct contact with the myocardium, which enables a common microcirculation allowing bidirectional signaling between the tissues. It is possible that a change in the balance of protective and damaging mediators produced by EAT is a major driver for myocardial dysfunction. Notably, EAT volume and thickness associate with increased pro-inflammatory secretome and with coronary artery disease (CAD). Purpose This aim of this study was to analyze the total transcriptome in EAT and relate putative differences between patient groups to metabolic parameters as well as ongoing medications. Methods Between 2011 and 2016, 44 patients (mean age 68.0 years, 18.2% women) had a biopsy taken from the epicardial fat during coronoray by-pass surgery (CABG, n=36), or during elective aortic valvular replacement due to aortic stenosis (AVR, n=8). RNA from epicardial fat biopsis was extracted and sequenced. Differentially expressed genes were obtained by custom scripts that performed a negative binomial distribution test on effective counts. Multivariate regression analysis with orthogonal partial least-squares-discriminant analysis (OPLS-DA) was applied to extract and interpret the systematic variation in the resolved RNA sequencing profiles. To identify enrichment of biologically relevant functional gene sets, our data were entered in evidence-based network enrichment analysis (EviNet). Results The CABG surgery was performed approximately 7 days after an acute coronary event (75% acute MI), and 44% of them had previously known CAD. None of the AVR cases had significant CAD. At surgery, 97% of the CABG cases were prescribed statins, and 36% of them had statins alredy before the actual admission (long-term statin treatment). 63% of the AVR cases were on statins at admission. The OPLS analysis revealed only one medication with significant outcome, i.e., patients with long-term treatment with statins (n=18) versus patients without (n=26). Long-term statin treatment associated with down-regulated gene expression involved in beta-oxidation and triglyceride biosynthesis whereas gene expression involved in extracellular matrix organization were up-regulated. Gene expression involved in MHC class II presentation and interferon signalling were also reduced in patients with long-term treatment with statisn. A downregulation of genes in the interleukin- and complement cascade genes among CABG patient (versus AVR patients) without long-term statin treatment showed normal levels in statin pretreated patients. Conclusion Long-term statin treatment has a major influence on transcriptional regulation of genes involved in beta-oxidation, triglyceride biosynthesis, extracellular matrix composition, MHC class II presentation and interferon signalling in epicardial adipose tissue. These findings support important metabolic and immune effects of statins beyond the lipid-lowering function.

Iron deficiency and all-cause mortality after myocardial infarction

Abstract Introduction Iron deficiency (ID) is commonly associated with cardiovascular diseases, including myocardial infarction (MI). However, the data on the clinical significance of ID in patients with MI are conflicting. This may be related to the use of various ID criteria. Purpose Our study aimed to compare the association of different ID criteria with all-cause mortality after MI. Methods Consecutive patients hospitalized at a large tertiary heart center for type 1 MI without previous history of coronary artery disease were included. We evaluated the association of different iron metabolism parameters measured on the first day after hospital admission with all-cause mortality during the follow-up. Results Of a cohort of 1,156 patients included (aged 64±12 years, 25% women), 194 (16.8%) died during the median follow-up of 3.4 years (IQR 626-1782 days). A total of 51,7% of post-MI patients had low iron levels (≤13 µmol/L), and 16,3% of them had iron level ≤12.8 µmol/L and soluble transferrin receptor (sTfR) ≥3 mg/L. After multivariate adjustment, iron level ≤13 µmol/L (HR 1.67, 95% CI 1.19-2.34) and the combination of iron level ≤12.8 µmol/L and sTfR ≥3 mg/L (HR 2.56, 95% CI 1.64-3.99) were associated with an increased risk of mortality. This information provided additional predictive value to the GRACE score. No association between ferritin level and mortality was found. Compared to the model which contains iron level, the addition of sTfR improved risk stratification (net reclassification improvement 0.61, 95% CI 0.52-0.69) by reclassifying patients into a higher-risk group. Conclusion ID is common among patients with the first MI. The criteria based on iron and soluble transferrin receptor levels provide the best prediction of mortality, and should be evaluated in future interventional studies with intravenous iron therapy.Kaplan-Meier survival for iron levelsK-M survival for combined ID parameters

Defining Golden Batches in Biomanufacturing Processes From Internal Metabolic Activity to Detect Process Changes That May Affect Product Quality.

Cellular metabolism plays a role in the observed variability of a drug substance's Critical Quality Attributes (CQAs) made by biomanufacturing processes. Therefore, here we describe a new approach for monitoring biomanufacturing processes that measures a set of metabolic reaction rates (named Critical Metabolic Parameters (CMP) in addition to the macroscopic process conditions currently being used as Critical Process Parameters (CPP) for biomanufacturing. Constraint-based systems biology models like Flux Balance Analysis (FBA) are used to estimate metabolic reaction rates, and metabolic rates are used as inputs for multivariate Batch Evolution Models (BEM). Metabolic activity was reproducible among batches and could be monitored to detect a deliberately induced macroscopic process shift (i.e., temperature change). The CMP approach has the potential to enable "golden batches" in biomanufacturing processes to be defined from the internal metabolic activity and to aid in detecting process changes that may impact the quality of the product. Overall, the data suggested that monitoring of metabolic activity has promise for biomanufacturing process control.

The Effect of Copper Nanoparticles on Liver Metabolism Depends on the Type of Dietary Fiber

Background/Objectives: A diet enriched with copper nanoparticles (CuNPs) exhibits a wide range of effects on liver metabolism, both positive and negative. Dietary fibers are the key components that may affect the absorption of minerals, including copper, and change their impact on organisms. Methods: Therefore, this study investigated whether and how supplementation with different sources of dietary fiber (cellulose, pectin, inulin, and psyllium) affects the function of CuNPs in the liver of male Wistar rats. Results: The results showed that CuNPs at different doses had varying effects on lipid metabolism and inflammation in the liver. Specifically, higher doses of CuNPs were associated with increased lipid accumulation and the activation of pro-inflammatory mechanisms. However, combining CuNPs with dietary fibers, such as psyllium and inulin, was beneficial in mitigating the effects of the examined nanoparticles, leading to reduced fat, cholesterol, and triglycerides in the liver. Combining psyllium with CuNPs showed the most substantial effect on liver metabolism and inflammation parameters. Furthermore, hepatic histology analyses showed that adding psyllium to the diet with CuNPs reduces changes associated with fat accumulation and mononuclear cell infiltration. The observed beneficial changes in the liver may have been related to a reduction in the gene expression level of sterol regulatory element-binding protein 1 and peroxisome proliferator-activated receptor gamma and cyclooxygenase-2. Conclusions: In conclusion, enriching the diet with dietary fibers such as psyllium can regulate the action of CuNPs, thereby improving lipid metabolism and reducing inflammation in the liver.

Can we skip invasive biopsy of sentinel lymph nodes? A preliminary investigation to predict sentinel lymph node status using PET/CT-based radiomics

BackgroundSentinel lymph node (SLN) biopsy (SLNB) is considered the gold standard for detecting SLN metastases in patients with invasive ductal breast cancer (IDC). However, SLNB is invasive and associated with several complications. Thus, this study aimed to evaluate the diagnostic performance of a non-invasive radiomics analysis utilizing 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT) for assessing SLN metastasis in IDC patients.MethodsThis retrospective study included 132 patients with biopsy-confirmed IDC, who underwent 18F-FDG PET/CT scans prior to mastectomy or breast-conserving surgery with SLNB. Tumor resection or SLNB was conducted within one-week post-scan. Clinical data and metabolic parameters were analyzed to identify independent SLN metastasis predictors. Radiomic features were extracted from each PET volume of interest (VOI) and CT-VOI. Feature selection involved univariate and multivariate logistic regression analysis, and the least absolute shrinkage and selection operator (LASSO) method. Three models were developed to predict SLN status using the random forest (RF), decision tree (DT), and k-Nearest Neighbors (KNN) classifiers. Model performance was assessed using the area under the receiver operating characteristic curve (AUC).ResultsThe study included 91 cases (32 SLN-positive and 59 SLN-negative patients) in the training cohort and 41 cases (29 SLN-positive and 12 SLN-negative patients) in the validation cohort. Multivariate logistic regression analysis identified Ki 67 and TLG as independent predictors of SLN status. Five PET-derived features, three CT-derived features, and two clinical variables were selected for model development. The AUC values of the RF, KNN, and DT models for the training cohort were 0.887, 0.849, and 0.824, respectively, and for the validation cohort were 0.856, 0.830, and 0.819, respectively. The RF model demonstrated the highest accuracy for the preoperative prediction of SLN metastasis in IDC patients.ConclusionThe PET-CT radiomics approach may offer robust and non-invasive predictors for SLN status in IDC patients, potentially aiding in the planning of personalized treatment strategies for IDC patients.

Simulating the methodological bias in the ATLS classification of hypovolemic shock: a critical reappraisal of the base deficit renaissance

BackgroundThe Advanced Trauma Life Support classification (ATLS) of hypovolemic shock is a widely used teaching and treatment reference in emergency medicine, but oversimplifies clinical reality. A decade ago, a landmark study compared vital parameters to base deficit (BD) in trauma patients. The investigators concluded that BD had higher accuracy to detect the need for early blood product administration. BD was subsequently introduced in the ATLS shock classification and has since been widely accepted as a laboratory standard for hypovolemia. The aim of this study is to investigate whether a methodological bias may have inadvertently contributed to the study’s results and interpretation.MethodsIn the current study, we replicate the original study by simulating a cohort of trauma patients with randomly generated data and applying the same methodological strategies. First, a predefined correlation between all predictor variables (vital parameters and BD) and outcome variable (transfusion) was set at 0.55. Then, in accordance with the methods of the original study we created a composite of ATLS parameters (highest class amongst heart rate, systolic blood pressure, and Glasgow Coma Scale) and compared it with BD for resulting transfusion quantity. Given the preset correlations between predictors and outcome, no predictor should exhibit a stronger association unless influenced by methodological bias.ResultsApplying the original imbalanced grouping and composite allocation strategies caused a systematic overestimation of shock class for traditional ATLS parameters, favoring the association between BD and transfusion. This effect persisted when the correlation between BD and transfusion was set substantially worse (rho = 0.3) than the correlation between ATLS parameters and transfusion (rho = 0.8).ConclusionsIn this fully reproducible simulation, we confirm the inadvertent presence of methodological bias. It is physiologically reasonable to include a metabolic parameter to classify hypovolemic shock, but more evidence is needed to support widespread and preferred use of BD.

Morus alba: natural and valuable effects in weight loss management

Overweight and obesity are conditions associated with serious comorbidities, such as diabetes and cardiovascular disease. Prevalence of excessive fat accumulation is increasing worldwide, and thus the need for efficient and sustainable weight loss regimes has become a major issue in clinical practice. Despite the important advances in the development of anti-obesity medications (AOM), their side effects, cost, and accessibility, are limiting factors for their routine use. Conversely, the studies of medicinal plants for weight management holds strong promise as a growing area of research. This review consolidates the representative evidence about the beneficial impacts of Morus alba on weight management and associated metabolic parameters, encompassing: inhibition of digestive enzymes, and thus contribution to the energy deficit required for weight loss, improvements in glucose and lipid metabolism, and attenuation of adiposity. Findings from in vitro, in vivo, and clinical investigations reviewed in the paper, demonstrate that white mulberry extracts have the potency to supplement efficiently and safely a healthy weight management approach.

Expression of PGC-1α, PPAR-α and UCP1 genes, metabolic and anthropometric factors in response to sodium butyrate supplementation in patients with obesity: a triple-blind, randomized placebo-controlled clinical trial.

There is increasing evidence that gut metabolites have a role in the etiology of obesity. This study aimed to investigate the effects of sodium butyrate (NaB) supplementation on the expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1α (PGC-1α), PPAR-α, and uncoupling protein-1 (UCP-1) genes, as well as on the metabolic parameters and anthropometric indices in persons with obesity. In this triple-blind placebo-controlled randomized clinical trial, 50 individuals with obesity were randomly assigned to NaB (600 mg/day) + hypo-caloric diet or placebo group + hypo-caloric diet for 8 weeks. The study measured the participants' anthropometric characteristics, food consumption, and feelings of hunger in addition to the serum levels of metabolic indices and the mRNA expression of the PGC-1α, PPAR-α, and UCP-1 genes in peripheral blood mononuclear cells (PBMCs). PGC-1α and UCP-1 genes expression significantly increased in NaB group compared to the placebo at the endpoint. A significant decrease in weight, BMI, and waist circumference (WC) was observed in NaB group. Among the metabolic factors, NaB significantly decreased fasting blood sugar (FBS) (P = 0.04), low-density lipoprotein cholesterol (LDL-C) (P = 0.038) and increased high-density lipoprotein cholesterol (HDL-C) (P = 0.016). NaB could not significantly change serum GLP-1 level. This study unveiled NaB supplementation alone cannot have significant beneficial effects on anthropometric, and biochemical factors. NaB could affect anthropometric and metabolic risk variables associated with obesity only when prescribed, along with calorie restriction. This study was registered in the Iranian Registry of Clinical Trials ( https://en.irct.ir/trial/53968 ) on 31 January 2021 (registry number IRCT20190303042905N2).

Skeletal muscle size and quality in healthy kidney donors, normal range and clinical associations

The gold standard to estimate muscle mass and quality is computed tomography (CT) scan. Lower mass and density (intramuscular fat infiltration) of skeletal muscles are markers of sarcopenia, associated with increased mortality risk, impaired physical function, and poorer prognosis across various populations and medical conditions. We aimed to describe standard reference values in healthy population, prospective kidney donors, and correlate clinical parameters to muscle mass and density. Included in the cohort 384 consecutive kidney donors. Mean age was 44.6 ± 11.5 (range 18.4–74.2), 46% were female and mean BMI was 25.6 ± 3.8 kg/m2. Our quantified reference values for psoas cross -sectional area (CSA) index at L3 level (males/females respectively) were 6.3 ± 1.8 and 4.8 ± 1.9 cm2 /m2, and density was 46.1 ± 5 and 41 ± 5 HU at that level. Older age (standardized beta coefficient − 0.12, p = 0.04), sex (− 0.32, p < 0.001) and BMI (0.17, p = 0.002) were significantly associated with CSA index of psoas at L3. Density, however, was associated with triglycerides level (− 0.21, p < 0.001), in addition to age (− 0.22, p < 0.0001), sex (− 0.27, p < 0.001) and BMI (− 0.1, p = 0.05). Our study validates the normative values of psoas muscle mass and density in healthy individuals and suggests correlations with clinical parameters. We demonstrate the significance of measuring not only the mass of the muscle, but also its density, as it has a valid association with metabolic parameters, including BMI and lipid level, even in healthy individuals and in the normal range of the tests.

Calcification in sea urchin larvae is associated with low metabolic costs.

The energetic costs to generate calcium carbonate skeletons and shells in marine organisms remain largely speculative due to the scarcity of empirical data. However, this information is critical to estimate energetic limitations of marine calcifiers that can explain their sensitivities to changes in sea water carbonate chemistry in past, present and future marine systems. The cost of calcification was evaluated using larval stages of the purple sea urchin, Strongylocentrotus purpuratus. We developed a skeleton re-mineralization assay, in which the skeleton was dissolved in live larvae followed by a re-mineralization over a few days. During skeleton re-mineralization, energetic costs were estimated through the measurement of key metabolic parameters including whole animal metabolic rates, citrate synthase (CS) enzyme activities and mRNA expression as well as mitochondrial densities in the calcifying primary mesenchyme cells (PMCs). Minor increases in a CS activity and a 10-15% increase in mitochondrial densities in PMCs were observed in re-mineralizing larvae as compared to control larvae. Re-mineralization under three different pH conditions (pH 8.1, pH 7.6 and pH 7.1) decreased with decreasing pH accompanied by pronounced increases in CS expression levels and increased mitochondrial densities in PMCs at pH 7.6. Despite a prominent increase in mitochondrial density of primary mesenchyme cells, particularly in the calcifying cohort of this cell type, this work demonstrated a low overall metabolic response to increased mineralization rates on the whole animal level under both, high and low pH conditions. We conclude that calcification in sea urchin larvae is compromised under low pH conditions, associated with low energetic efforts to fuel compensatory processes.