The Promise of Cilnidipine in Hypertension with Comorbidities: National Consensus Statement: National Consensus Group Comprises Cardiologists, Nephrologists, and Diabetologists from India in a National Meet at New Delhi held on 22nd May 2022.

The rapidly increasing burden of hypertension is responsible for premature deaths from cardiovascular disease (CVD), renal disease, and stroke, with a tremendous public health and financial burden. Hypertension detection, treatment, and control vary worldwide; it is still low, particularly in low- and middle-income countries (LMICs). High blood pressure (BP) and CVD risk have a strong, linear, and independent association. They contribute to alarming numbers of all-cause and CVD deaths. A major culprit for increased hypertension is sympathetic activity, and further complications of hypertension are heart failure, ischemic heart disease (IHD), stroke, and renal failure. Now, antihypertensive interventions have emerged as a global public health priority to reduce BP-related morbidity and mortality. Calcium channel blockers (CCB) are highly effective vasodilators. and the most common drugs used for managing hypertension and CVD. Cilnidipine, with both L- and N-type calcium channel blocking activity, is a promising 4th generation CCB. It causes vasodilation via L-type calcium channel blockade and inhibits the sympathetic nervous system (SNS) via N-type calcium channel blockade. Cilnidipine, which acts as a dual L/N-type CCB, is linked to a reduced occurrence of pedal edema compared to amlodipine, which solely blocks L-type calcium channels. The antihypertensive properties of cilnidipine are very substantial, with low BP variability and long-acting properties. It is beneficial for hypertensive patients to deal with morning hypertension and for patients with abnormal nocturnal BP due to exaggerated sympathetic nerve activation. Besides its BP-lowering effect, it also exhibits organ protection via sympathetic nerve inhibition and renin-angiotensin-aldosterone system inhibition; it controls heart rate and proteinuria. Reno-protective, neuroprotective, and cardioprotective effects of cilnidipine have been well-documented and demonstrated.

Long-term Stroke and Mortality Risk in Nonagenarians Following Transcatheter Aortic Valve Insertion.

BACKGROUND: Limited data exist on the long-term outcomes of transcatheter aortic valve insertion (TAVI) in nonagenarian patients. The purpose of this study is to investigate the relationship between patient baseline comorbidity and frailty on the long-term outcome of the nonagenarian population. METHODS: Retrospective analysis of 187 consecutive nonagenarian patients who underwent TAVI from 2009 to 2020. Multivariable models were utilized to analyze the association between basleline patient and frailty variables and mortality, stroke, and repeat hospitalization. Long-term survival was compared to an age- and sex-matched US population. RESULTS: The median STS-predicted risk of mortality (STS-PROM) was 10% (IQR, 7-17%). Frailty was met in 72% of patients based on the five-meter walk test, 13% based on KCCQ-12 score, 12% based on KATZ activities of daily living, and 8% based on serum albumin levels. Procedure-related mortality occured in 3 (2%) patients and stroke in 8 (4%). The median duration of follow-up was 3.4 years. Outcomes included death in 150 (80%) patients, stroke in 15, and repeat hospitalization in 114. Multivariable analysis identified no association between any of the baseline patient variables with mortality, stroke, repeat hospitalization, or the combined outcomes (all P>0.05). One- and five-year survival rates in TAVI-treated nonagenarians were similar to age- and sex-matched controls (P=0.27). CONCLUSIONS: Long-term death or stroke is independent of STS-PROM and frailty risk variables in this nonagenarian patient population who received TAVI. Furthermore, survival is similar to age- and sex-matched controls.

Native freshwater lake microbial community response to an in situ experimental dilbit spill.

With the increase in crude oil transport throughout Canada, the potential for spills into freshwater ecosystems has increased and additional research is needed in these sensitive environments. Large enclosures erected in a lake were used as mesocosms for this controlled experimental dilbit (diluted bitumen) spill under ambient environmental conditions. The microbial response to dilbit, the efficacy of standard remediation protocols on different shoreline types commonly found in Canadian freshwater lakes, including a testing of a shoreline washing agent were all evaluated. We found that the native microbial community did not undergo any significant shifts in composition after exposure to dilbit or the ensuing remediation treatments. Regardless of the treatment, sample type (soil, sediment, or water), or type of associated shoreline, the community remained relatively consistent over a 3-month monitoring period. Following this, metagenomic analysis of polycyclic aromatic and alkane hydrocarbon degradation mechanisms also showed that while many key genes identified in PAH and alkane biodegradation were present, their abundance did not change significantly over the course of the experiment. These results showed that the native microbial community present in a pristine freshwater lake has the prerequisite mechanisms for hydrocarbon degradation in place, and combined with standard remediation practices in use in Canada, has the genetic potential and resilience to potentially undertake bioremediation.

Polygenic Risk Score Assessment for Coronary Artery Disease in Asian Indians.

We evaluated the performance of various polygenic risk score (PRS) models derived from European (EU), South Asian (SA), and Punjabi Asian Indians (AI) studies on 13,974 subjects from AI ancestry. While all models successfully predicted Coronary artery disease (CAD) risk, the AI, SA, and EU + AI were superior predictors and more transportable than the EU model; the predictive performance in training and test sets was 18% and 22% higher in AI and EU + AI models, respectively than in EU. Comparing individuals with extreme PRS quartiles, the AI and EU + AI captured individuals with high CAD risk showed 2.6 to 4.6 times higher efficiency than the EU. Interestingly, including the clinical risk score did not significantly change the performance of any genetic model. The enrichment of diversity variants in EU PRS improves risk prediction and transportability. Establishing population-specific normative and risk factors and inclusion into genetic models would refine the risk stratification and improve the clinical utility of CAD PRS.

Influence of heavy Canadian crude oil on pristine freshwater boreal lake ecosystems in an experimental oil spill.

The overall impact of a crude oil spill into a pristine freshwater environment in Canada is largely unknown. To evaluate the impact on the native microbial community, a large-scale in situ model experimental spill was conducted to assess the potential role of the natural community to attenuate hydrocarbons. A small volume of conventional heavy crude oil (CHV) was introduced within contained mesocosm enclosures deployed on the shoreline of a freshwater lake. The oil was left to interact with the shoreline for 72 h and then free-floating oil was recovered using common oil spill response methods (i.e. freshwater flushing and capture on oleophilic absorptive media). Residual polycyclic aromatic hydrocarbon (PAH) concentrations returned to near preoiling concentrations within 2 months, while the microbial community composition across the water, soil, and sediment matrices of the enclosed oligotrophic freshwater ecosystems did not shift significantly over this period. Metagenomic analysis revealed key polycyclic aromatic and alkane degradation mechanisms also did not change in their relative abundance over the monitoring period. These trends suggest that for small spills (<2 l of oil per 15 m2 of surface freshwater), physical oil recovery reduces polycyclic aromatic hydrocarbon concentrations to levels tolerated by the native microbial community. Additionally, the native microbial community present in the monitored pristine freshwater ecosystem possesses the appropriate hydrocarbon degradation mechanisms without prior challenge by hydrocarbon substrates. This study corroborated trends found previously (Kharey et al. 2024) toward freshwater hydrocarbon degradation in an environmentally relevant scale and conditions on the tolerance of residual hydrocarbons in situ.

Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-RKT.

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRSL274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-RKT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-RKT/ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-RKT to promote proliferation and subsequent muscle resilience during CR.

Long-range optical coherence tomography of pediatric airway during drug induced sleep endoscopy: A preliminary report.

OBJECTIVE: Drug induced sleep endoscopy (DISE) is often performed for pediatric obstructive sleep apnea (OSA) when initial diagnostic studies do not provide adequate information for therapy. However, DISE scoring is subjective and with limitations. This proof-of-concept study demonstrates the use of a novel long-range optical coherence tomography (LR-OCT) system during DISE of two pediatric patients. METHODS: LR-OCT was used to visualize the airway of pediatric patients during DISE. At the conclusion of DISE, the OCT probe was guided in the airway under endoscopic visual guidance, and cross-sectional images were acquired at the four VOTE locations. Data processing involved image resizing and alignment, followed by rendering of three-dimensional (3D) volumetric models of the airways. RESULTS: Two patients were included in this study. Patient one had 18.4%, 20.9%, 72.3%, and 97.3% maximal obstruction at velum, oropharynx, tongue base, and epiglottis, while patient two had 40.2%, 41.4%, 8.0%, and 17.5% maximal obstruction at these regions, respectively. Three-dimensional reconstructions of patients' airways were also constructed from the OCT images. CONCLUSION: This proof-of-concept study demonstrates the successful evaluation of pediatric airway during DISE using LR-OCT, which accurately identified sites and degrees of obstruction with respective 3D airway reconstruction.

Ensembl 2024.

Ensembl (https://www.ensembl.org) is a freely available genomic resource that has produced high-quality annotations, tools, and services for vertebrates and model organisms for more than two decades. In recent years, there has been a dramatic shift in the genomic landscape, with a large increase in the number and phylogenetic breadth of high-quality reference genomes, alongside major advances in the pan-genome representations of higher species. In order to support these efforts and accelerate downstream research, Ensembl continues to focus on scaling for the rapid annotation of new genome assemblies, developing new methods for comparative analysis, and expanding the depth and quality of our genome annotations. This year we have continued our expansion to support global biodiversity research, doubling the number of annotated genomes we support on our Rapid Release site to over 1700, driven by our close collaboration with biodiversity projects such as Darwin Tree of Life. We have also strengthened support for key agricultural species, including the first regulatory builds for farmed animals, and have updated key tools and resources that support the global scientific community, notably the Ensembl Variant Effect Predictor. Ensembl data, software, and tools are freely available.

Advanced Interface Engineering in Gradient Core/Shell Quantum Dots Enables Efficient Photoelectrochemical Hydrogen Evolution.

Semiconductor core/shell quantum dots (QDs) are considered promising building blocks to fabricate photoelectrochemical (PEC) cells for the direct conversion of solar energy into hydrogen (H2). However, the lattice mismatch between core and shell in such QDs results in undesirable defects and severe carrier recombination, limiting photo-induced carrier separation/transfer and solar-to-fuel conversion efficiency. Here, an interface engineering approach is explored to minimize the core-shell lattice mismatch in CdS/CdSexS1-x (x = 0.09-1) core/shell QDs (g-CSG). As a proof-of-concept, PEC cells based on g-CSG QDs yield a remarkable photocurrent density of 13.1 mA cm-2 under AM 1.5 G one-sun illumination (100 mW cm-2), which is ≈54.1% and ≈33.7% higher compared to that in CdS/CdSe0.5S0.5 (g-CSA) and CdS/CdSe QDs (g-CS), respectively. Theoretical calculations and carrier dynamics confirm more efficient carrier separation and charge transfer rate in g-CSG QDs with respect to g-CSA and g-CS QDs. These results are attributed to the minimization of the core-shell lattice mismatch by the cascade gradient shell in g-CSG QDs, which modifies carrier confinement potential and reduces interfacial defects. This work provides fundamental insights into the interface engineering of core/shell QDs and may open up new avenues to boost the performance of PEC cells for H2 evolution and other QDs-based optoelectronic devices.

Assessing the prediction of type 2 diabetes risk using polygenic and clinical risk scores in South Asian study populations.

Background: Genome-wide polygenic risk scores (PRS) have shown high specificity and sensitivity in predicting type 2 diabetes (T2D) risk in Europeans. However, the PRS-driven information and its clinical significance in non-Europeans are underrepresented. We examined the predictive efficacy and transferability of PRS models using variant information derived from genome-wide studies of Asian Indians (AIs) (PRSAI) and Europeans (PRSEU) using 13,974 AI individuals. Methods: Weighted PRS models were constructed and analyzed on 4602 individuals from the Asian Indian Diabetes Heart Study/Sikh Diabetes Study (AIDHS/SDS) as discovery/training and test/validation datasets. The results were further replicated in 9372 South Asian individuals from UK Biobank (UKBB). We also assessed the performance of each PRS model by combining data of the clinical risk score (CRS). Results: Both genetic models (PRSAI and PRSEU) successfully predicted the T2D risk. However, the PRSAI revealed 13.2% odds ratio (OR) 1.80 [95% confidence interval (CI) 1.63-1.97; p = 1.6 × 10-152] and 12.2% OR 1.38 (95% CI 1.30-1.46; p = 7.1 × 10-237) superior performance in AIDHS/SDS and UKBB validation sets, respectively. Comparing individuals of extreme PRS (ninth decile) with the average PRS (fifth decile), PRSAI showed about two-fold OR 20.73 (95% CI 10.27-41.83; p = 2.7 × 10-17) and 1.4-fold OR 3.19 (95% CI 2.51-4.06; p = 4.8 × 10-21) higher predictability to identify subgroups with higher genetic risk than the PRSEU. Combining PRS and CRS improved the area under the curve from 0.74 to 0.79 in PRSAI and 0.72 to 0.75 in PRSEU. Conclusion: Our data suggest the need for extending genetic and clinical studies in varied ethnic groups to exploit the full clinical potential of PRS as a risk prediction tool in diverse study populations.

Multi-omic rejuvenation and life span extension on exposure to youthful circulation.

Heterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on biological age and long-term health is unknown. Here we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the epigenetic age of blood and liver based on several clock models using two independent platforms. Remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a global multi-omic rejuvenation effect. In addition, old HPB mice showed gene expression changes opposite to aging but akin to several life span-extending interventions. Altogether, we reveal that long-term HPB results in lasting epigenetic and transcriptome remodeling, culminating in the extension of life span and health span.

Random matrix theory tools for the predictive analysis of functional magnetic resonance imaging examinations.

Purpose: Random matrix theory (RMT) is an increasingly useful tool for understanding large, complex systems. Prior studies have examined functional magnetic resonance imaging (fMRI) scans using tools from RMT, with some success. However, RMT computations are highly sensitive to a number of analytic choices, and the robustness of findings involving RMT remains in question. We systematically investigate the usefulness of RMT on a wide variety of fMRI datasets using a rigorous predictive framework. Approach: We develop open-source software to efficiently compute RMT features from fMRI images and examine the cross-validated predictive potential of eigenvalue and RMT-based features ("eigenfeatures") with classic machine-learning classifiers. We systematically vary pre-processing extent, normalization procedures, RMT unfolding procedures, and feature selection and compare the impact of these analytic choices on the distributions of cross-validated prediction performance for each combination of dataset binary classification task, classifier, and feature. To deal with class imbalance, we use the area under the receiver operating characteristic curve (AUROC) as the main performance metric. Results: Across all classification tasks and analytic choices, we find RMT- and eigenvalue-based "eigenfeatures" to have predictive utility more often than not (82.4% of median AUROCs>0.5; median AUROC range across classification tasks 0.47 to 0.64). Simple baseline reductions on source timeseries, by contrast, were less useful (58.8% of median AUROCs>0.5, median AUROC range across classification tasks 0.42 to 0.62). Additionally, eigenfeature AUROC distributions were overall more right-tailed than baseline features, suggesting greater predictive potential. However, performance distributions were wide and often significantly affected by analytic choices. Conclusions: Eigenfeatures clearly have potential for understanding fMRI functional connectivity in a wide variety of scenarios. The utility of these features is strongly dependent on analytic decisions, suggesting caution when interpreting past and future studies applying RMT to fMRI. However, our study demonstrates that the inclusion of RMT statistics in fMRI investigations could improve prediction performances across a wide variety of phenomena.

Patient-Reported Status and Heart Failure Outcomes in Asia by Sex, Ethnicity, and Socioeconomic Status.

Background: In heart failure (HF), symptoms and health-related quality of life (HRQoL) are known to vary among different HF subgroups, but evidence on the association between changing HRQoL and outcomes has not been evaluated. Objectives: The authors sought to investigate the relationship between changing symptoms, signs, and HRQoL and outcomes by sex, ethnicity, and socioeconomic status (SES). Methods: Using the ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) Registry, we investigated associations between the 6-month change in a "global" symptoms and signs score (GSSS), Kansas City Cardiomyopathy Questionnaire overall score (KCCQ-OS), and visual analogue scale (VAS) and 1-year mortality or HF hospitalization. Results: In 6,549 patients (mean age: 62 ± 13 years], 29% female, 27% HF with preserved ejection fraction), women and those in low SES groups had higher symptom burden but lower signs and similar KCCQ-OS to their respective counterparts. Malay patients had the highest GSSS (3.9) and lowest KCCQ-OS (58.5), and Thai/Filipino/others (2.6) and Chinese patients (2.7) had the lowest GSSS scores and the highest KCCQ-OS (73.1 and 74.6, respectively). Compared to no change, worsening of GSSS (>1-point increase), KCCQ-OS (≥10-point decrease) and VAS (>1-point decrease) were associated with higher risk of HF admission/death (adjusted HR: 2.95 [95% CI: 2.14-4.06], 1.93 [95% CI: 1.26-2.94], and 2.30 [95% CI: 1.51-3.52], respectively). Conversely, the same degrees of improvement in GSSS, KCCQ-OS, and VAS were associated with reduced rates (HR: 0.35 [95% CI: 0.25-0.49], 0.25 [95% CI: 0.16-0.40], and 0.64 [95% CI: 0.40-1.00], respectively). Results were consistent across all sex, ethnicity, and SES groups (interaction P > 0.05). Conclusions: Serial measures of patient-reported symptoms and HRQoL are significant and consistent predictors of outcomes among different groups with HF and provide the potential for a patient-centered and pragmatic approach to risk stratification.

Magnetic and Biocompatible Polyurethane Nanofiber Biomaterial for Tissue Engineering.

Recruitment of endothelial cells to cardiovascular device surfaces could solve issues of thrombosis, neointimal hyperplasia, and restenosis. Since current targeting strategies are often nonspecific, new technologies to allow for site-specific cell localization and capture in vivo are needed. The development of cytocompatible superparamagnetic iron oxide nanoparticles has allowed for the use of magnetism for cell targeting. In this study, a magnetic polyurethane (PU)-2205 stainless steel (2205-SS) nanofibrous composite biomaterial was developed through analysis of composite sheets and application to stent-grafts. The PU nanofibers provide strength and elasticity while the 2205-SS microparticles provide ferromagnetic properties. Sheets were electrospun at mass ratios of 0-4:1 (2205-SS:PU) and stent-grafts with magnetic or nonmagnetic stents were coated at the optimal ratio of 2:1. These composite materials were characterized by microscopy, mechanical testing, a sessile drop test, magnetic field measurement, magnetic cell capture assays, and cytocompatibility after 14 days of culturing with endothelial cells. Results of this study show that an optimal ratio of 2:1 2205-SS:PU results in a hydrophobic material that balanced mechanical and magnetic properties and was cytocompatible up to 14 days. Significant cell capture required a thicker material of 0.5 mm thickness. Stent-grafts fabricated from a magnetic coating and a magnetic stent demonstrated uniform cell capture throughout the device surface. This novel biomaterial exhibits a combination of mechanical and magnetic properties that enables magnetic capture of cells and other therapeutic agents for vascular and other tissue engineering applications.