Low Plasma Research Articles

Spatially resolved plasma composition evolution in a solar flare – The effect of reconnection outflow

Context. Solar flares exhibit complex variations in elemental abundances compared to photospheric values. These abundance variations, characterized by the first ionization potential (FIP) bias, remain challenging to interpret. Aims. We aim to (1) examine the spatial and temporal evolution of coronal abundances in the X8.2 flare on 2017 September 10, and (2) provide a new scenario to interpret the often observed high FIP bias loop top, and provide further insight into differences between spatially resolved and Sun-as-a-star flare composition measurements. Methods. We analyzed 12 Hinode/Extreme-ultraviolet Imaging Spectrometer (EIS) raster scans spanning 3.5 hours, employing both Ca XIV 193.87 Å/Ar XIV 194.40 Å and Fe XVI 262.98 Å/S XIII 256.69 Å composition diagnostics to derive FIP bias values. We used the Markov Chain Monte Carlo (MCMC) differential emission measure (DEM) method to obtain the distribution of plasma temperatures, which forms the basis for the FIP bias calculations. Results. Both the Ca/Ar and Fe/S composition diagnostics consistently show that flare loop tops maintain high FIP bias values of > 2–6, with peak phase values exceeding 4, over the extended duration, while footpoints exhibit photospheric FIP bias of ∼1. The consistency between these two diagnostics forms the basis for our interpretation of the abundance variations. Conclusions. We propose that this variation arises from a combination of two distinct processes: high FIP bias plasma downflows from the plasma sheet confined to loop tops, and chromospheric evaporation filling the loop footpoints with low FIP bias plasma. Mixing between these two sources produces the observed gradient. Our observations show that the localized high FIP bias signature at loop tops is likely diluted by the bright footpoint emission in spatially averaged measurements. The spatially resolved spectroscopic observations enabled by EIS prove critical for revealing this complex abundance variation in loops. Furthermore, our observations show clear evidence that the origin of hot flare plasma in flaring loops consists of a combination of both directly heated plasma in the corona and from ablated chromospheric material; and our results provide valuable insights into the formation and composition of loop top brightenings, also known as EUV knots, which are a common feature at the tops of flare loops.

Maternal separation alters peripheral immune responses associated with IFN-γ and OT in mice.

The co-evolution of social behavior and the immune system plays a critical role in individuals' adaptation to their environment. However, also need for further research on the key molecules that co-regulate social behavior and immunity. This study focused on neonatal mice that were separated from their mothers for 4hours per day between the 6th and 16th day after birth. The results showed that these mice had lower plasma levels of IFN-γ and oxytocin, but higher levels of plasma glucocorticoids (GC), then impacting their social abilities. Additionally, maternal separation led to decreased levels of BDNF, IGF2, and CREB mRNAs in the hippocampus, while levels in the prefrontal cortex (PFC) remained unaffected. Maternal separation also resulted in increased levels of oxytocin and CRH mRNA in the hypothalamus, as well as an increase in CD45+ lymphocyte subsets in the meninges and choroid plexus (CP), with CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP showing an increase. In IFN-γ-/- mice, a decrease in social preference was observed alongside lower plasma oxytocin levels. Moreover, IFN-γ-/- mice exhibited reduced numbers of oxytocin neurons in the paraventricular nucleus of the paraventricular nucleus of hypothalamus (PVN), decreased BDNF levels in the PFC and hippocampus, and alterations in CD45+ lymphocytes in CP and meninges, with an increase in CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP. These findings highlight the immunological impact of social stress on IFN-γ regulation, suggesting that the immunomodulatory molecule IFN-γ may influence social behavior by affecting synaptic efficiency in brain regions such as the hippocampus and PFC, which are linked to oxytocin in the PVN.

Constraints on the accretion properties of quasi-periodic erupters from GRMHD simulations

Some apparently quiescent supermassive black holes (BHs) at centers of galaxies show quasi-periodic eruptions (QPEs) in the X-ray band, the nature of which is still unknown. A possible origin for the eruptions is an accretion disk. However, the properties of such disks are restricted by the timescales of recurrence and the duration of the flares. In this work, we test the possibility that the temporal properties of known QPEs can be explained by accretion from a compact accretion disk with an outer radius out g and we focus on a particular object, GSN 069. We ran several 3D general relativistic magnetohydrodynamic (GRMHD) simulations with the H-AMR code of thin and thick disks and studied how the initial disk parameters such as thickness, magnetic field configuration, magnetization, and Kerr parameter affect the observational properties of QPEs. We show that accretion onto a slowly rotating BH through a small, moderately thin accretion disk with an initially low plasma beta can explain the observed time between outbursts and the lack of evidence for a variable jet emission. In order to form such a disk, the accreting matter should have a low net angular momentum. A potential source for such low angular momentum matter with a quasi-periodic feeding mechanism might be a tight binary of wind-launching stars. Apart from their primary application, our results can also be useful for general studies of systems with small accretion disks, in which evolution occurs very rapidly so that the disks cannot be considered stationary. For such systems, it is important to understand how the initial conditions affect the results.

Adiponectin and Risk of Psoriasis: Observational and Mendelian Randomization Studies in up to 900 000 Individuals.

Psoriasis is a chronic inflammatory skin disorder often associated with obesity. Adiponectin, an anti-inflammatory protein-hormone secreted by adipose tissue, may be a link between obesity and psoriasis. We hypothesized that low plasma adiponectin is associated with an increased risk of psoriasis in observational and causal genetic studies. In observational analyses, we used information on plasma adiponectin and psoriasis in 30 045 individuals from the Copenhagen General Population Study (CGPS). In one-sample Mendelian randomization analyses, we used genetic information on adiponectin and psoriasis in 107 308 individuals from the CGPS. In two-sample Mendelian randomization analyses, we used genetic information on adiponectin from the ADIPOGen consortium and genetic information on psoriasis in 373 338 and 462 933 individuals from the FinnGen study and UK Biobank (UKB). In observational analyses, a 1-unit log-transformed higher plasma adiponectin was associated with a hazard ratio (HR) for psoriasis of 0.67 (95% confidence interval: 0.48-0.94) in an age- and sex-adjusted model but not in a multivariable adjusted model including obesity measures with a HR of 0.95 (0.66-1.35). In genetic one-sample Mendelian randomization analysis, a 1-unit log-transformed higher plasma adiponectin was not associated with a causal risk ratio for psoriasis of 1.33 (0.77-2.32) in the CGPS. In two-sample Mendelian randomization analyses, a 1-unit log-transformed higher plasma adiponectin was not associated with causal risk ratios for psoriasis of 0.96 (0.81-1.14) in FinnGen and 1.00 (1.00-1.01) in UKB. Low plasma adiponectin is associated with increased risk of psoriasis in age- and sex-adjusted observational analyses; however, this was not the case after adjustment for obesity measures or in causal genetic analyses.

Exploring mitochondrial blood-based and genetic markers in older adults with mild cognitive impairment and remitted major depressive disorder

Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer’s disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ2 = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ2 = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI.

The association of plasma homocysteine levels with short-term mortality in sepsis patients: A meta-analysis.

The association between plasma homocysteine (Hcy) levels and short-term mortality in sepsis patients remains unclear. This meta-analysis aimed to clarify this potential relationship. Following PRISMA 2020 and Cochrane Handbook guidelines, we conducted a comprehensive literature search in the PubMed, Embase, and Web of Science databases up to June 24, 2024. We included cohort studies that assessed the association between plasma Hcy levels and all-cause mortality in adult sepsis patients. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model to account for potential heterogeneity. Nine cohort studies involving 771 sepsis patients were included. Overall, no significant difference in plasma Hcy levels was observed between survivors and non-survivors (SMD: -0.23, 95% CI: -0.84 to 0.37, P = 0.45), with substantial heterogeneity (I² = 86%). Subgroup analysis revealed lower plasma Hcy levels among survivors in Chinese patients (SMD: -1.56, 95% CI: -1.98 to -1.13, P < 0.001) but not in non-Asian patients. Plasma Hcy levels were not significantly associated with all-cause mortality (OR per 1-unit increment: 1.03, 95% CI: 0.95 to 1.11, P = 0.51), with notable heterogeneity (I² = 72%). However, a significant association was found in Chinese patients (OR: 1.09, 95% CI: 1.03 to 1.15, P = 0.003), but not in non-Asian patients. In conclusion, plasma Hcy levels were not generally associated with short-term mortality in sepsis patients. However, significant associations were observed in Chinese patients, suggesting potential ethnic differences that warrant further investigation.

Relationship between renin, aldosterone, aldosterone-to-renin ratio and left ventricular mass index in young adults

Abstract Background Primary aldosteronism (PA), characterised by excessive aldosterone production and mineralocorticoid receptor activation, is associated with adverse cardiovascular outcomes including left ventricular hypertrophy and failure. Elevated cardiovascular risk is observed even in milder and subclinical forms of PA, especially in middle-aged and elderly populations. It is unclear if early changes in PA biomarkers can affect left ventricular mass index (LVMI), which is a strong predictor of cardiovascular diseases. Aim To evaluate the relationship between PA biomarkers, namely renin concentration, aldosterone concentration and aldosterone-to-renin ratio (ARR), and LVMI in young adults. Methods The Raine Study is a longitudinal, population-based cohort study in Western Australia that enrolled women during pregnancy. We analysed the data from the offspring of these women at age 27. Participants with PA biomarkers and LVMI measured by cardiac magnetic resonance imaging were included. Females who were on oral contraception were excluded due to its confounding effect on the ARR. We examined the relationship between LVMI and plasma renin, aldosterone, and ARR using multivariate-adjusted linear regression and used mediation analysis to test whether these relationships were dependent on systolic blood pressure (SBP). Results Of 758 participants, 252 (33.2%) were females and the mean (SD) age was 26.7 (0.4) years. Females had lower median plasma renin concentration (12.0 vs 15.4mU/L; p&amp;lt;0.001) and higher median ARR (21.0 vs 15.6; p&amp;lt;0.001) than males. There was no sex-difference in median plasma aldosterone concentration (257 vs 237pmol/L in males; p=0.143). Females had lower LVMI (52.2 vs 70.2 g/m²; p&amp;lt;0.001) than males. A significant association between LVMI and aldosterone was detected in males (β-coefficient 0.009; 95% CI 0.001 to 0.017; p=0.027), and between LVMI and ARR in females (β-coefficient 0.098; 95% CI 0.001 to 0.196; p=0.050) after adjusting for confounders. This relationship was not mediated by brachial SBP. Conclusion An elevated aldosterone concentration or ARR was associated with higher LVMI in young adults, independent of brachial SBP. Long-term follow-up is required to determine if the relationship persists over time and leads to reduced cardiac function. One may speculate that an intervention trial in young adults with subclinical PA is warranted to determine the role of aldosterone blockade in preventing future cardiovascular diseases.

Lipoprotein(a) regulates vascular redox state and inflammatory response in patients with coronary artery disease

Abstract Background Circulating Lipoprotein(a) (Lp(a)) is associated with cardiovascular disease, and over 90% of its variation in plasma is genetically determined. However, neither the causal nature of this association nor the underlying mechanisms are fully documented. Purpose We explored the hypothesis that Lp(a) triggers atherogenesis by dysregulating vascular redox-sensitive inflammatory state. Methods 1027 patients with advanced coronary artery disease (CAD) undergoing cardiac surgery were genotyped and a genetic signature (LPA) determining Lp(a) levels was generated. RNA-sequencing and vascular superoxide (O2.-) measurements were performed in internal mammary arteries (IMA), and the contribution of NADPH-oxidases and uncoupled endothelial nitric oxide synthase (eNOS) were determined. Patients were followed up for a median of 5.07 years. Results A genetic screening identified 7 SNPs (LPA) that were associated with increased Lp(a) plasma levels (A). Patients in the alternative LPA variant group, as well as patients with higher plasma Lp(a) levels, had significantly higher basal arterial O2.-. Patients with diabetes had significantly lower plasma Lp(a) compared to non-diabetics and the association between plasma Lp(a) and arterial O2.- was driven by non-diabetic patients. The effect of Lp(a) on vascular redox state was primarily due to eNOS uncoupling, resulting from reduced vascular tetrahydrobiopterin (BH4) bioavailability. Indeed, patients in the alternative LPA variant group or with higher plasma Lp(a) levels had a greater arterial eNOS-derived (LNAME-inhibitable) O2.- production (B,C). Levels of eNOS essential cofactor BH4 (defined by the ratio of plasma BH4 to its oxidation product BH2) were lower in patients with higher plasma Lp(a) levels (D). There was no significant impact of Lp(a) variability on vascular NADPH oxidase-derived O2.-. RNA sequencing of arterial tissue revealed dysregulation of nitrosative and inflammatory signalling in patients with high Lp(a), although there was no association with systemic biomarkers of inflammation (i.e. hsCRP) or oxidative stress (i.e. malondialdehyde). Finally, both LPA and high plasma Lp(a) were associated with elevated risk for cardiovascular mortality (E,F). When the cox regression models were additionally corrected for arterial O2.- production, both the models for the LPA genetic signature (HR[95% CI]=2.053[0.180-23.428], p=0.563) and plasma Lp(a) (HR[95% CI]=1.700[0.325-8.885], p=0.529) lost significance. This implies that redox-sensitive inflammatory signalling may be a link between Lp(a) and cardiovascular risk. All above associations were independent from plasma ApoB. Conclusions This study demonstrates for the first time that a genetically determined increase in plasma Lp(a) results in dysregulated vascular redox/nitrosative signalling in patients with atherosclerosis, revealing new therapeutic opportunities in cardiovascular prevention.

Flecainide acetate inhalation solution for cardioversion of recent-onset, symptomatic atrial fibrillation: results of the phase 3 RESTORE-1 trial

Abstract Introduction Safe, rapid, and efficacious drugs for acute cardioversion of paroxysmal AF (PAF) are needed. In an open-label, Phase 2 study (INSTANT), orally inhaled flecainide was safe and efficacious for acute conversion of PAF to sinus rhythm (SR).[1, 2] Purpose Evaluate the efficacy and safety of flecainide acetate inhalation solution (FlecIH-103) compared to placebo in patients with short-duration, symptomatic, newly diagnosed, or recurrent PAF. Methods RESTORE-1 was a multicentre, randomized, double-blind, placebo-controlled trial in patients with symptomatic PAF (≤48 hours). Patients received FlecIH-103 at an estimated total lung dose of 120 mg or placebo (3:1) over 8 minutes using a breath-actuated nebulizer and were continuously monitored for 90 minutes (observation period), using a single-lead patch ECG electrode. Results The study was stopped prematurely after 55 of the expected 400 patients had been enrolled due to lower-than-expected flecainide peak plasma levels (197.8 ng/mL; 1.85-fold lower than those observed with the same target dose in INSTANT) and modest efficacy. The Data Monitoring Committee confirmed that there were no safety risks. Fifty-four of the enrolled patients (42 active; 12 placebo) were in AF at the start of inhalation. Baseline characteristics were well-balanced between treatment groups; overall mean age was 59.6 years (SD: 13.5) and 31.5% of patients were female. Cardioversion rates during the observation period in the efficacy population (n=51; 39 active, 12 placebo) were 30.8% (95% CI: 18.5-46.5%) in the active group and 0% (95% CI: 0.0-28.2%) in the placebo group (p=0.04; figure 1). In the active group, the median time to conversion from start of inhalation was 12.8 minutes (IQR: 7.8-25.0 minutes), which includes an 8-minute inhalation period. Among the 12 patients whose AF converted to SR, only 1 (8.3%) still had AF-related symptoms compared to 71.8% of patients whose AF did not convert to SR (p&amp;lt;0.001). Time to discharge-eligible status was 1.6h for patients whose AF cardioverted and 3.3h for those whose AF did not (p=0.002; figure 2). The most common adverse events (AEs; ≥8%) occurring more frequently in the active than the placebo group were the following: dyspnoea (14.3%), dysgeusia (14.3%) and cough (11.9%). No serious AEs or cardiovascular events of special interest (hypotension, ventricular tachycardia, bradycardia, sinus pause, atrial flutter 1:1, other arrhythmias) were reported. Conclusions Orally inhaled flecainide, at approximately half of the targeted dose, was modestly effective and safe. The 1.5-fold lower conversion rate observed in this study, compared to the same dose in the INSTANT trial, is consistent with the lower plasma levels of flecainide achieved. Future studies will be designed to improve drug delivery to yield peak plasma levels of flecainide associated with higher conversion rates.

Serum transferrin concentration: a new prognostic biomarker in heart failure with reduced ejection fraction

Abstract Introduction Iron deficiency (ID) is a common comorbidity in patients with reduced heart failure (HFrEF), and is associated with poor clinical status and outcomes, but there is not enough data investigating serum transferrin concentration (STC) as a biomarker HFrEF to predict prognosis and mortality. Purpose We investigated relationship between STC at admission and all-cause mortality during follow-up in HFrEF. Methods We reviewed the medical data of 420 patients hospitalised in our institution for HFrEF over a period of 18 months. Laboratory tests were performed on the first 24 hours of admission. Patients were divided into two groups according to STC, using the value of 199 μg/dl as the cut-off. This value was determined from the ROC analysis to be the value with the highest sensitivity and specificity. Then we analysed relationship between STC at admission and all-cause mortality during follow-up between the two groups, after adjustment of the various variables described in the literature. Results Of 420 patients with HFrEF, 18.6% had STC ≤ 199 μg/dl (group 1) and 81.4% had STC &amp;gt; 199 μg/dl (group 2) with no difference in age and sex distribution (p = 0.873 ; p = 0.304). Patients with low STC were more likely to be diabetic (70.5% vs 46.5% ; p &amp;lt; 0.001), have dyslipidemia (52.6% vs 33%; p = 0.002), and history of chronic renal failure (6.4% vs 2.0% ; p = 0.045). There was no relation between STC and NYHA class (p = 0.776), hospital stay (p = 0.491) nor EF (p = 0.146). Biologically, lower STC was significantly associated with higher serum ferritin (292.77 vs 198.17 ; p &amp;lt; 0.001), TSAT (68.30 vs 22.21 ; p = 0.020) and C-reactive protein (CRP) (124.91 vs 39.98 ; p = &amp;lt; 0.001), lower plasma B-type natriuretic peptide (BNP) (5798.32 vs 6449.97 ; p = 0.002), with no difference in haemoglobin level (p = 0.272) and estimated glomerular filtration rate (eGFR) (p = 0.260). The prevalence of iron deficiency by the ESC criteria was lower in those with low STC; ferritin &amp;lt; 100 μg/l (15.4% vs 29.2% ; p = 0.015) or TSAT &amp;lt; 20% (33.3% vs 51,8% ; p = 0.004). There was no difference between the two groups in term of NYHA class and EF at three months (p = 0.87, p = 0.108). However, all-cause mortality during follow-up was significantly associated with low STC (37.2% vs 17.0% ; p &amp;lt;0.001). (Figure 1) In multivariable analysis, all-cause mortality was independently associated with STC ≤ 199 μg/dl (HR 1.71; 95% CI : 1.08 ; 2.7 ; p = 0.02). This is the same finding for the ischaemic origin of HFrEF (HR 2.1 ; p = 0.001), therapeutic inertia during follow-up (HR 5.53 ; p &amp;lt;0.001) and EF &amp;lt; 36% (HR 1.03 ; p = 0.047) (Figure 2). Conclusion More data are required before the routine use of STC as a biomarker of prognosis in HFrEF, but it may represent a reliable and cost-effective option to predict mortality.FIGURE 1FIGURE 2

Cost-effectiveness analysis of implementing the Nagasaki Acute Myocardial Infarction (AMI) secondary prevention clinical pathway

Abstract Background/Introduction Because of the poor prognosis associated with acute coronary syndromes (ACS), intensive low-density lipoprotein cholesterol (LDL-C) management therapy is recommended as early as possible after the onset of ACS, with the goal of lowering plasma LDL-C to &amp;lt;70 mg/dL. In Nagasaki City, a council was formed comprising all hospitals performing percutaneous coronary intervention along with general physicians, and an initiative to manage LDL-C using a region-wide LDL-C management clinical pathway (Figure 1) was launched in July 2022. The rate of intensive statin therapy at discharge increased from 34.5% to 79.8%, and the rate of patients achieving LDL-C &amp;lt;70 mg/dL at discharge increased from 37.2% to 54.6% following the implementation of the clinical pathway. However, the cost-effectiveness of implementing the clinical pathway remains to be determined. Purpose: The purpose of this study was to evaluate the cost-effectiveness of implementing the Nagasaki AMI Secondary Prevention Clinical Pathway. Methods: To evaluate the cost-effectiveness of implementing the clinical pathway compared with no implementation, a lifetime simulation was performed using mathematical models. The models consisted of a decision tree model to model the flow of the clinical pathway (Figure 2) and a Markov model to consider the risks of developing cardiovascular disease (CVD) events. The quality-adjusted life year (QALY) was used as the outcome. Drug costs and treatment costs for each CVD event were included. Drug costs were calculated from actual prescriptions. Treatment costs and utility scores for each event were based on the literature. The risk of each CVD event was calculated using baseline risks estimated using commercial claims data (DeSC Healthcare, Inc.) and patients' LDL-C levels at discharge and 1 month after discharge. LDL-C levels at each time point were set separately for the groups that achieved or did not achieve a discharge LDL-C &amp;lt; 70 mg/dL, for patients with and without implementing the clinical pathway. Results: Implementing the clinical pathway was evaluated as dominant, with an incremental gain of 0.079 QALYs per person and expected cost savings of JPY 103,124 per person. Implementing the clinical pathway was shown to not only provide additional health benefits by preventing CVD, but also to reduce future health care costs. In the analysis with a 10-year time horizon, the result remained dominant, and the same level of cost savings was expected. Conclusions: Implementing the Nagasaki AMI Secondary Prevention Clinical Pathway can be expected to reduce costs, in addition to increasing QALYs by preventing CVD. Further clinical and economic evaluation of long-term follow-up with a collaborative pathway to the general physician after discharge from the hospital is expected.

Plasma statin concentrations do not correlate with statin-induced myalgia

Abstract Aims Statins are essential in cardiovascular prevention. Although well-tolerated, patient adherence is often suboptimal due to experienced musculoskeletal symptoms ranging from mild myalgia to rare life-threatening rhabdomyolysis. This study aimed to investigate the relationship between plasma concentrations of statin metabolites in patients experiencing myalgia without rhabdomyolysis. Methods and results Plasma concentrations of statin metabolites were quantitatively assessed using mass spectrometry across three case-control cohorts evaluating statin-induced myalgia. The analysis included a total of 373 patients from the MILANO study (N=85 with self -reported myalgia), the MONTREAL study (N=248 with clinically verified myalgia) and the STOMP study (N=40 with rechallenge-verified statin-induced myalgia). STOMP found no significant difference in the plasma concentrations of statin metabolites between statin naïve patients with myalgia (N=12) taking atorvastatin 80 mg daily and asymptomatic controls (N=28), including upon subsequent statin rechallenge. Both the MILANO and MONTREAL studies showed lower plasma concentrations of statin metabolites in patients with myalgias compared to controls. MILANO showed a significant difference in rosuvastatin lactone concentration in patients with myalgias compared to asymptomatic controls (P = 0.025). Similarly, MONTREAL showed significantly lower mean atorvastatin metabolite concentrations in affected patients versus controls (P values ranging from 0.0073 to 0.037). Atorvastatin dosages in MONTREAL ranged from 5 to 80 mg daily, the most frequent regimens being 20 mg (27% in cases; 24% in controls) and 40 mg (33% in cases; 37% in controls). Creatine kinase levels were measured in all cohorts and were not different between cases and controls. Conclusion Development of myalgias in patients with normal creatine kinase levels is not associated with higher statin metabolite plasma concentrations. Myalgias during statin therapy are not caused by pharmacokinetic abnormalities.

Exploring the Impact of Pharmacological Target-Mediated Low Plasma Exposure in Lead Compound Selection in Drug Discovery – A Modeling Approach

Exploring the Impact of Pharmacological Target-Mediated Low Plasma Exposure in Lead Compound Selection in Drug Discovery – A Modeling Approach

Neonatal hypoglycemia: A review with focus on practical challenges and recent updates on management

At birth, a neonate undergoes a transition from the continuous maternal supply of glucose to a variable and intermittent oral glucose intake, which is regulated by the interplay of hormones and metabolic enzyme induction. Because low plasma glucose concentrations are common in the neonatal period, it may be difficult to identify those who have pathologic hypoglycemia. Hence, it is important to formally evaluate such babies by drawing critical samples. Here, we present two cases of neonatal hypoglycemia where the presentation had some similarities, but the comprehensive evaluation revealed a varied etiological spectrum necessitating lifelong management. Through these case studies, authors discuss practical challenges in the diagnosis, management, and follow-up of neonates with endocrine causes of hypoglycemia.

Renal Semaphorin 3C mediates cardiac adaptive response

Abstract Cardiorenal syndrome, characterized by reciprocal heart-kidney interactions that progressively promote dysfunction in both organs, is associated with a high mortality rate. However, the mechanisms linking the two organs are insufficiently understood. Here we report that semaphorin 3C (SEMA3C) is a novel cardioprotective mediator secreted from the kidney. SEMA3C was highly expressed in the renal proximal tubules in mice. Renal Sema3c expression and circulating SEM3C were reduced by the left ventricular pressure overload that induced renal remodeling. Proximal tubule-specific secretory Sema3c deletion exacerbated cardiac hypertrophy, fibrosis and dysfunction after the pressure overload, suggesting renal SEMA3C is important for the proper cardiac adaptive response. Mechanistically, SEMA3C inhibits pathological cardiac remodeling at least partly by inhibiting Akt, ERK and Wnt/β-catenin signaling in cardiomyocytes. In heart failure patients, the plasma SEMA3C level was decreased and the low plasma SEMA3C was associated with poor cardiac outcomes. Collectively, our results show that SEMA3C produced by the kidney pivotally contributes to the cardiac stress response and its reduction contributes to the progression of heart failure. SEMA3C signaling appears to be an attractive therapeutic and diagnostic target for cardiorenal syndrome.

Effect of Statins and Renin–Angiotensin–Aldosterone System Inhibitors on IL-6 Levels in COVID-19 Patients

Background/Objectives: Severe clinical course and mortality from COVID-19 are mostly associated with increased concentrations of IL-6 and IL-10. Findings from clinical trials suggest that both statins and renin–angiotensin–aldosterone system inhibitors (RAASI) might have the potential to reduce unfavorable outcomes in patients with COVID-19. The aim of this study was to evaluate the effect of statins and RAASI on the cytokine concentrations in COVID-19 patients. Methods: SARS-CoV-2 infected patients were enrolled in this study, and demographic, clinical, and routine laboratory data were evaluated. Plasma cytokine levels were measured by multiplex assay. Results: COVID-19 patients with chronic cardiovascular diseases (CVD) had significantly lower median plasma IL-6 levels than COVID-19 patients with no co-morbidities (26 vs. 53 pg/mL, p = 0.021). COVID-19 patients with CVD who were taking statins had significantly lower median concentrations of IL-6 (21 vs. 44 pg/mL, p = 0.027), TNFα (21 vs. 39.5 pg/mL, p = 0.036), and IL-10 (19 vs. 25.5 pg/mL, p = 0.025) compared to COVID-19 patients with no CVD. In a binary logistic regression model, IL-6 was a significant variable, with an odds ratio value of 0.961 (95% CI 0.929–0.995). Regarding RAASI, only plasma IL-6 (22 vs. 44 pg/mL, p = 0.012) levels were found to be significantly lower in COVID-19 patients with CVD consuming these medications compared to patients who did not have any CVD. Conclusions: COVID-19 patients who had chronic cardiovascular co-morbidities and who were administered statins or RAASI had significantly lower concentrations of IL-6 than COVID-19 patients who did not have any co-morbidities. These findings suggest that the use of statins or RAASI may be of value in COVID-19 patients.

Eco-Friendly High Microporosity Low Temperature Plasma Exposed Activated Carbon from Coconut Shell For nano Hybrid Super Capacitors

Abstract This study looked at the structural, chemical, and electrochemical properties of coconut shell activated carbon (CSAC) before and after plasma treatment. Structural analysis using X-ray diffraction (XRD) demonstrated that plasma treatment improves graphitic structure by plans at (002) and (101) for higher angles. Chemical investigation utilizing Fourier-transform infrared spectroscopy (FTIR) revealed an increase in hydroxyl groups and carboxylic content following plasma treatment, which enhances electrochemical performance. Raman spectroscopy revealed a drop in the ID/IG ratio from 1.00 to 0.90, indicating enhanced graphitic order. Scanning electron microscopy (FESEM) showed that plasma treatment improves surface shape, while elemental analysis assessed the high carbon content (76.56% by weight). Contact angle measurements showed a decrease from 114° to 65°, showing improved hydrophilicity after treatment. Electrochemical investigation shows that the plasma-treated CSAC had a maximum specific capacitance of 1612 F/g, compared to 729 F/g for the untreated CSAC, and a total capacitance of plasma treated1685 F/g are untreated 1400 F/g. The cyclic stability tests indicated that the plasma-treated CSAC retained 94% capacitance and 98% coulombic efficiency after 3000 cycles, which is superior to the untreated CSAC's 92% capacitance retention and 95% coulombic efficiency. This reveals that plasma-treated CSAC has significantly improved performance and stability, making it an excellent alternative for high-performance and cost-effective energy storage applications.

Use of Lupinus albus as a Local Protein Source in the Production of High-Quality Iberian Pig Products

The replacement of soybean meal with sweet white lupin (Lupinus albus L.) seeds was investigated in the diets of Iberian pigs during the growing and fattening phases, evaluating its effects on growth performance, carcass traits, and meat quality. Iberian pigs (n = 50) were divided into two dietary groups (n = 25 per group), receiving either a lupin-based concentrate or a soybean meal-based concentrate. The data were analysed using one-way analysis of variance (ANOVA), with a significance level of p &lt; 0.05. The results showed that lupin substitution had no adverse effect on body weight, average daily gain, or carcass characteristics. No significant differences were observed in meat quality parameters such as pH, colour, and texture. However, significantly (p = 0.007) lower levels of saturated fatty acids (SFA) content were found in the intramuscular fat of pre-finishing (primor) pigs fed lupin-based diets. In addition, these pigs had lower plasma triglyceride levels at the end of the growing phase. Overall, the results suggest that sweet white lupin is a viable alternative protein source in Iberian pig production, offering potential health benefits in line with consumer preferences for sustainably produced, healthier meat products, without compromising production efficiency or product quality.

RF pulsed plasma modified composite scaffold for enhanced anti-microbial activity and accelerated wound healing

Infected wounds present significant challenges pertaining to healing and often demand administration of strong antibiotics to patients. Also, drug resistant microbes may alter the physiology of wounds to create biofilms, frequently leading to high morbidity and mortality. In this investigation, a biodegradable, microporous composite agarose-chitosan scaffold was fabricated. Furthermore, its surface was modified with diphenyldiselenide deposition, using low pressure pulsed plasma technology. The optimized plasma parameters, viz. 5ON/15OFF (ms) of plasma pulse rate and 80 min of treatment time resulted in scaffolds having enhanced anti-bacterial activity against gram positive microbes like Staphylococcus (S.) aureus and S. epidermidis. The scaffolds were non-toxic to skin cells, as confirmed by the MTT assay. Cell proliferation through plasma treated and native scaffolds was assessed by culturing primary human dermal fibroblasts (HdaF) and human keratinocytes (HaCaT) and visualizing via confocal microscopy. Moreover, in-vivo rat model confirmed accelerated wound healing with plasma treated scaffold (100 % on day 14), as compared to the native scaffold (100 % on day 16) when compared with over-the-counter (OTC) ointment Betadine (100 % on day 12).

Passivating and low damaging plasma etching of GaN using Cl2 and SiCl4 for recessed gate MOSc-HEMT devices

Passivating and low damaging plasma etching of GaN using Cl2 and SiCl4 for recessed gate MOSc-HEMT devices