Mineralocorticoid receptor antagonists and atrial fibrillation: a meta-analysis of clinical trials.

BACKGROUND AND AIMS: Mineralocorticoid receptor antagonists (MRAs) improve cardiovascular outcomes in a variety of settings. This study aimed to assess whether cardioprotective effects of MRAs are modified by heart failure (HF) and atrial fibrillation (AF) status and to study their impact on AF events. METHODS: MEDLINE, Embase, and Cochrane Central databases were searched to 24 March 2023 for randomized controlled trials evaluating the efficacy of MRAs as compared with placebo or usual care in reducing cardiovascular outcomes and AF events in patients with or at risk for cardiovascular diseases. Random-effects models and interaction analyses were used to test for effect modification. RESULTS: Meta-analysis of seven trials (20 741 participants, mean age: 65.6 years, 32% women) showed that the efficacy of MRAs, as compared with placebo, in reducing a composite of cardiovascular death or HF hospitalization remains consistent across patients with HF [risk ratio = 0.81; 95% confidence interval (CI): 0.67-0.98] and without HF (risk ratio = 0.84; 95% CI: 0.75-0.93; interaction P = .77). Among patients with HF, MRAs reduced cardiovascular death or HF hospitalization in patients with AF (hazard ratio = 0.95; 95% CI: 0.54-1.66) to a similar extent as in those without AF (hazard ratio = 0.82; 95% CI: 0.63-1.07; interaction P = .65). Pooled data from 20 trials (21 791 participants, mean age: 65.2 years, 31.3% women) showed that MRAs reduce AF events (risk ratio = 0.76; 95% CI: 0.67-0.87) in both patients with and without prior AF. CONCLUSIONS: Mineralocorticoid receptor antagonists are similarly effective in preventing cardiovascular events in patients with and without HF and most likely retain their efficacy regardless of AF status. Mineralocorticoid receptor antagonists may also be moderately effective in preventing incident or recurrent AF events.

Aldosterone and aldosterone synthase inhibitors in cardiorenal disease.

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.

Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction.

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.

Fractal characterizations of MeV ion treated CaF2 thin films.

We present the morphological evolution and fractal characterizations of CaF2 thin-film surfaces modified by bombardment with 100 MeV Au+8 ions at various fluences. Atomic force microscopy (AFM) combined with line profile and two-dimensional power spectral density (2D-PSD) analysis was utilized to investigate the evolution of surface morphology as a function of fluence. The AFM images were utilized to investigate the relationship between fractal dimension, roughness exponent, lateral correlation length, and ion fluence. The surface erosion owing to sputtering was depicted using Rutherford backscattering spectrometry. The structural characteristics' dependency on fluence was explored with the help of glancing angle x-ray diffraction measurements on virgin and irradiated samples. Tensile stress calculated using a peak shift in the glancing angle x-ray diffractogram showed an increase in tensile stress with fluence that caused the surface to crack after the fracture strength of the surface was crossed. 2D-PSD analysis signified the role of sputtering over surface diffusion for the observed surface modifications. Fractal dimensions first increased and then decreased with ion fluence. The lateral correlation length decreased, while the roughness exponent increased with fluence after the threshold value.

Sequencing and de novo transcriptome assembly for discovering regulators of gene expression in Jack (Artocarpus heterophyllus).

Jack (Artocarpus heterophyllus) is a multipurpose fruit-tree species with minimal genomic resources. The study reports developing comprehensive transcriptome data containing 80,411 unigenes with an N50 value of 1265 bp. We predicted 64,215 CDSs from the unigenes and annotated and functionally categorized them into the biological process (23,230), molecular function (27,149), and cellular components (17,284). From 80,411 unigenes, we discovered 16,853 perfect SSRs with 192 distinct repeat motif types reiterating 4 to 22 times. Besides, we identified 2741 TFs from 69 TF families, 53 miRNAs from 19 conserved miRNA families, 25,953 potential lncRNAs, and placed three functional eTMs in different lncRNA-miRNA pairs. The regulatory networks involving genes, TFs, and miRNAs identified several regulatory and regulated nodes providing insight into miRNAs' gene associations and transcription factor-mediated regulation. The comparison of expression patterns of some selected miRNAs vis-à-vis their corresponding target genes showed an inverse relationship indicating the possible miRNA-mediated regulation of the genes.

Formulation and performance evaluation of polymeric mixed micelles encapsulated with baicalein for breast cancer treatment.

The present study is aimed to formulate baicalein-loaded mixed micelles to enhance the solubility and oral bioavailability. Baicalein encapsulated D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and pluronic F127 (F127) combined micelles were prepared and investigated for anticancer effect. The optimized formulation contains 25.04 ± 0.24 nm mean particle size of micelles with a zeta potential value of -4.01 ± 0.5 mV. The calculated entrapment efficiency percentage of baicalein within the micellar structure was 83.43 ± 0.13% and the in vitro release of baicalein from micelles displayed a sustained release profile at pH 7.4. The incorporation of baicalein within micelles core was also confirmed by FTIR analysis of formulation, which hardly represents the characteristic peak of baicalein, indicating successful entrapment of the drug. In vitro cell culture experiments revealed baicalein-loaded micelles significantly enhanced cellular uptake and cytotoxicity against MDAMB-231 cell lines in comparison to free baicalein. Additionally, as compared to free baicalein, baicalein micelles demonstrated greater apoptosis-inducing potential while the results of the cell cycle study exhibited arrest of cells at the G0/G1 phase of the cell cycle. Results of ROS (reactive oxygen species) and MMP (mitochondrial membrane potential) assay revealed the ROS-dependent mitochondrial-mediated apoptosis pathway utilized by developed formulation to inhibit cell proliferation. Thus, the developed nano micelles can serve as a potent carrier system for baicalein against breast cancer.

A new clustering method for the diagnosis of CoVID19 using medical images.

With the spread of COVID-19, there is an urgent need for a fast and reliable diagnostic aid. For the same, literature has witnessed that medical imaging plays a vital role, and tools using supervised methods have promising results. However, the limited size of medical images for diagnosis of CoVID19 may impact the generalization of such supervised methods. To alleviate this, a new clustering method is presented. In this method, a novel variant of a gravitational search algorithm is employed for obtaining optimal clusters. To validate the performance of the proposed variant, a comparative analysis among recent metaheuristic algorithms is conducted. The experimental study includes two sets of benchmark functions, namely standard functions and CEC2013 functions, belonging to different categories such as unimodal, multimodal, and unconstrained optimization functions. The performance comparison is evaluated and statistically validated in terms of mean fitness value, Friedman test, and box-plot. Further, the presented clustering method tested against three different types of publicly available CoVID19 medical images, namely X-ray, CT scan, and Ultrasound images. Experiments demonstrate that the proposed method is comparatively outperforming in terms of accuracy, precision, sensitivity, specificity, and F1-score.

Evaluation of forewarning models for mustard aphids in different agro-climatic zones of India.

Mustard aphid, Lipaphis erysimi (Kaltenbach), is the most serious pest of Rapeseed-Mustard which is known to be responsible for a tremendous loss in yield and oil content, under various agro-climatic conditions of India. Information support on aphid occurrence and intensity is necessary for effective management by the farmers in the mustard-growing belt. In this study, an effort is made to develop forewarning model using the field data on aphid for 12 consecutive rabi seasons from 2003-2004 to 2014-2015 under different agro-climatic locations in India. Three main components of aphid-related stages were identified for which necessary forewarnings were needed to be issued: (1) severity, (2) the time of reaching the economic threshold level (ETL) for decision-making on pesticide application, and (3) time of occurrence of peak population. To address these, three different models were developed/used and validated using incident field dataset. Those field observations when the infestation level were below severe category (< 60) during rising phase of the aphid population were found to indicate highest R sqr. (0.82) for the model-I during validation. When model-II was used, 11 out of 14 locations (78.57%) stood validated. The assumptions made in model-III also got validated when humidity thermal ratio (HTR) of the week of peak population ranged between 1.5 and 4 (lowest among the weeks considered), and population reached severe category. The models showed better results during real-time validation in seasons 2016-2017 and 2017-2018, thus suggesting that these three models can be used to ascertain the severity, week of ETL, and week of peak aphid population for Brassica juncea varieties all over the mustard belt in India and can be operationalized spatially to forewarn against the aphid pest population in future under Gramin Krishi Mausam Sewa (GKMS) scheme.

Marker-trait association for low-light intensity tolerance in rice genotypes from Eastern India.

Light intensity is a crucial environmental factor that affects photosynthesis and ultimately, grain yield in rice. However, no gene or marker directly associated with improved performance under low-light intensity under field conditions has been identified till date. With an aim of identifying genes and markers associated with improved performance (measured in terms of better yields) under low-light intensity, an integrated field screening, in silico and wet lab validation analysis was performed. Field-based screening of a diverse set of 110 genotypes led to the identification of two physiological and three morphological parameters critical for low-light tolerance in rice. In silico analysis using information available in public databases led to the identification of a set of 90 potential candidate genes which were narrowed to thirteen genic targets for possible marker-trait association. Marker-trait association on the panel of 48 diverse rice genotypes varying in their response to low-light intensity led to the identification of six markers [HvSSR02-44 (biological yield), HvSSR02-52 (spikelet fertility), HvSSR02-54 (grain yield), HvSSR06-56 (spikelet fertility), HvSSR06-69 (spikelet fertility; biological yield), HvSSR09-45 (spikelet fertility)] lying on chromosomes 2, 6 and 9 showing significant association (R2 > 0.1) for traits like grain yield/plant, biological yield and spikelet fertility under low light. Eight rice genes [including member of BBX (B-box) family] lying within 10 kb distance of these identified markers already reported for their role in response to stress or change in plant architecture in rice were also identified. The eight rice genotypes, five traits, eight genes and six markers identified in the current study will help in devising strategies to increase yield under low light intensity and pave way for future application in marker-assisted breeding.

The emerging role of proprotein convertase subtilisin/kexin type-9 inhibition in secondary prevention: from clinical trials to real-world experience.

PURPOSE OF REVIEW: The recent advent of a highly efficacious class of low-density lipoprotein cholesterol (LDL-C) lowering agents, the proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors, has transformed dyslipidaemia management in patients with cardiovascular disease as well as those with familial hypercholesterolemia. RECENT FINDINGS: Recent positive results of the landmark Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk cardiovascular outcome trial with evolocumab as an add-on to statin therapy demonstrate further reduction of cardiovascular events. Additional safety outcomes from this large randomized trial, as well as the EBBINGHAUS substudy, allay fears of neurocognitive disorder as an adverse effect of achieving very low LDL-C levels with these agents. SUMMARY AND IMPLICATIONS: Widespread clinical adoption of PCSK9 inhibitors will depend on the results from ongoing and planned cardiovascular efficacy and safety trials with PCSK9 inhibitors. In addition, understanding the practical challenges and barriers to usage of these injectable agents by high cardiovascular risk patients will also affect clinical adoption of this class of agents. Analysis of cost-benefit models, along with anticipated updates to practice guidelines for dyslipidaemia management are likely to strengthen the clinical utility of PCSK9 inhibitors. Importantly, the potency of this new class of agents provides a huge opportunity to extend further the 'lower LDL-C is better' hypothesis in an effort to reduce rates of cardiovascular morbidity and mortality on a population level.