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Heart Rhythm Apr 2024Catheter ablation of atrial fibrillation (AF) is an established therapy that reduces AF burden, improves quality of life, and reduces the risks of cardiovascular... (Review)
Review
Catheter ablation of atrial fibrillation (AF) is an established therapy that reduces AF burden, improves quality of life, and reduces the risks of cardiovascular outcomes. Although there are clear guidelines for the application of de novo catheter ablation, there is less evidence to guide recommendations for repeat catheter ablation in patients who experience recurrent AF. In this review, we examine the rationale for repeat ablation, mechanisms of recurrence, patient selection, optimal timing, and procedural strategies. We discuss additional important considerations, including treatment of comorbidities and risk factors, risk of complications, and effectiveness. Mechanisms of recurrent AF are often due to non-pulmonary vein (non-PV) triggers; however, there is insufficient evidence supporting the routine use of empiric lesion sets during repeat ablation. The emergence of pulsed field ablation may alter the safety and effectiveness of de novo and repeat ablation. Extrapolation of data from randomized trials of de novo ablation does not optimally inform efficacy in cases of redo ablation. Additional large, randomized controlled trials are needed to address important clinical questions regarding procedural strategies and timing of repeat ablation.
Topics: Humans; Atrial Fibrillation; Quality of Life; Treatment Outcome; Pulmonary Veins; Catheter Ablation; Recurrence
PubMed: 38101500
DOI: 10.1016/j.hrthm.2023.12.003 -
Frontiers in Chemistry 2023Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization... (Review)
Review
Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization process, dnDD is naturally categorized as a many-objective optimization problem (ManyOOP), where more than three objectives must be simultaneously optimized. However, a large number of objectives typically pose several challenges that affect the choice and the design of optimization methodologies. Herein, we cover the application of multi- and many-objective optimization methods, particularly those based on Evolutionary Computation and Machine Learning techniques, to enlighten their potential application in dnDD. Additionally, we comprehensively analyze how molecular properties used in the optimization process are applied as either objectives or constraints to the problem. Finally, we discuss future research in many-objective optimization for dnDD, highlighting two important possible impacts: i) its integration with the development of multi-target approaches to accelerate the discovery of innovative and more efficacious drug therapies and ii) its role as a catalyst for new developments in more fundamental and general methodological frameworks in the field.
PubMed: 38192501
DOI: 10.3389/fchem.2023.1288626 -
Kidney International Reports Sep 2023Belimumab was recently approved for treating lupus nephritis (LN), yet LN cases during belimumab treatment given for nonrenal causes have been reported. Identification...
INTRODUCTION
Belimumab was recently approved for treating lupus nephritis (LN), yet LN cases during belimumab treatment given for nonrenal causes have been reported. Identification of reliable signals of impending flare is imperative.
METHODS
We evaluated belimumab efficacy in preventing renal flares and factors associated with renal flare occurrence in nephritis-naïve patients with systemic lupus erythematosus (SLE) who are receiving add-on belimumab or placebo in 5 phase 3 clinical trials using Cox regression analysis.
RESULTS
Of 1844 eligible patients, 136 (7.4%) developed a renal flare during a 52-week long follow-up. Asian origin (Adjusted Hazard Ratio [HR]: 1.97; 95% confidence interval [CI]: 1.32-2.94; = 0.001), positive baseline anti-double stranded DNA (anti-dsDNA) levels (HR: 1.32; 95% CI: 1.07-1.63; = 0.008), and increasing mean prednisone dose during follow-up (HR: 1.03; 95% CI: 1.02-1.04; < 0.001) were associated with renal flares. Low-dose intravenous (IV) belimumab (1 mg/kg monthly) yielded a nearly 3-fold lower hazard of renal flare (HR: 0.38; 95% CI: 0.20-0.73; = 0.004). Subcutaneous (SC) belimumab (200 mg weekly) also yielded a lower hazard (HR: 0.69; 95% CI: 0.54-0.88; = 0.003). The labeled IV dose (10 mg/kg monthly) conferred no clear protection (HR: 0.74; 95% CI: 0.50-1.09; = 0.127).
CONCLUSION
We corroborated the substantial vulnerability of the Asian SLE population to renal affliction. Add-on low-dose IV belimumab (1 mg/kg) and SC belimumab appeared protective against renal flares in nephritis-naïve patients with SLE. The approved IV dose (10 mg/kg) yielded no clear protection.
PubMed: 37705915
DOI: 10.1016/j.ekir.2023.06.021 -
Yi Chuan = Hereditas Sep 2023The impending global climate change presents significant challenges to agricultural production. It is imperative to find approaches to ensure sustained growth in food... (Review)
Review
The impending global climate change presents significant challenges to agricultural production. It is imperative to find approaches to ensure sustained growth in food production while reducing agricultural input, in order to meet the needs of worldwide people for nutritious food supply. One of the effective strategies to address this challenge is still the development of new crop varieties with high yield, stable yield, environmental friendliness and rich nutrition. The creation of new crop cultivars depends largely on the expansion of genetic resources and the innovation of breeding techniques. domestication is an innovative breeding strategy for developing new crop varieties. It involves utilizing undomesticated or semi-domesticated plants with desirable traits as founder species for breeding. The process involves rapid domestication of wild plants through the redesign of agronomic traits and the introduction of domestication genes to meet diverse human needs. In this review, we overview the history of crop domestication and genetic improvement, clarify the necessity of enriching crop diversity, and emphasize the significance of wild plants' genetic diversity in expanding the scope for crop redesign. Breeding strategy innovation is the key to accelerate crop breeding. We also discuss the feasibility and prospects of rapid developing new crops through domestication.
Topics: Humans; Domestication; Plant Breeding; Agriculture; Crops, Agricultural; Phenotype
PubMed: 37731229
DOI: 10.16288/j.yczz.23-194 -
ENeuro Oct 2023The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the and salvage synthesis pathways. In the...
The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the and salvage synthesis pathways. In the embryonic central nervous system (CNS), the pathway is considered crucial to meet the requirements for the active proliferation of neural stem/progenitor cells (NSPCs). However, how these two pathways are balanced or separately used during CNS development remains poorly understood. In this study, we showed a dynamic shift in pathway utilization, with greater reliance on the pathway during embryonic stages and on the salvage pathway in postnatal-adult mouse brain. The pharmacological effects of various purine synthesis inhibitors and the expression profile of purine synthesis enzymes indicated that NSPCs in the embryonic cerebrum mainly use the pathway. Simultaneously, NSPCs in the cerebellum require both the and the salvage pathways. administration of inhibitors resulted in severe hypoplasia of the forebrain cortical region, indicating a gradient of purine demand along the anteroposterior axis of the embryonic brain, with cortical areas of the dorsal forebrain having higher purine requirements than ventral or posterior areas such as the striatum and thalamus. This histologic defect of the neocortex was accompanied by strong downregulation of the mechanistic target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase (S6K)/S6 signaling cascade, a crucial pathway for cell metabolism, growth, and survival. These findings indicate the importance of the spatiotemporal regulation of both purine pathways for mTORC1 signaling and proper brain development.
Topics: Mice; Animals; Purines; Homeostasis; Brain; Mechanistic Target of Rapamycin Complex 1
PubMed: 37770184
DOI: 10.1523/ENEURO.0159-23.2023 -
Frontiers in Endocrinology 2023The role of age in metastatic disease, including breast cancer, remains obscure. This study was conducted to determine the role of age in patients with metastatic...
BACKGROUND
The role of age in metastatic disease, including breast cancer, remains obscure. This study was conducted to determine the role of age in patients with metastatic breast cancer.
METHODS
Breast cancer patients diagnosed with distant metastases between 2010 and 2019 were retrieved from the Surveillance, Epidemiology, and End Results database. Comparisons were performed between young (aged ≤ 40 years), middle-aged (41-60 years), older (61-80 years), and the oldest old (> 80 years) patients. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using multivariate Cox proportional hazard models. Survival analysis was performed by the Kaplan-Meier method.
RESULTS
This study included 24155 (4.4% of all patients) metastatic breast cancer patients. The number of young, middle-aged, older, and the oldest old patients were 195 (8.3%), 9397 (38.9%), 10224 (42.3%), and 2539 (10.5%), respectively. The 5-year OS rate was highest in the young (42.1%), followed by middle-aged (34.8%), older (28.3%), and the oldest old patients (11.8%). Multivariable Cox regression analysis showed that middle-aged (aHR, 1.18; 95% CI, 1.10-1.27), older (aHR, 1.42; 95% CI, 1.32-1.52), and the oldest old patients (aHR, 2.15; 95% CI, 1.98-2.33) had worse OS than young patients. Consistently, middle-aged (aHR, 1.16; 95% CI, 1.08-1.25), older (aHR, 1.32; 95% CI, 1.23-1.43), and the oldest old patients (aHR, 1.86; 95% CI, 1.71-2.03) had worse BCSS than young patients.
CONCLUSION
This study provided clear evidence that metastatic breast cancer had an age-specific pattern. Age was an independent risk factor for mortality in patients with metastatic breast cancer.
Topics: Aged, 80 and over; Middle Aged; Humans; Female; Breast Neoplasms; Prognosis; Neoplasm Staging; Kaplan-Meier Estimate; Survival Analysis
PubMed: 38027167
DOI: 10.3389/fendo.2023.1184895 -
Trends in Plant Science Mar 2024Most high-yielding crops are susceptible to abiotic and biotic stresses, making them particularly vulnerable to the potential effects of climate change. A possible... (Review)
Review
Most high-yielding crops are susceptible to abiotic and biotic stresses, making them particularly vulnerable to the potential effects of climate change. A possible alternative is to accelerate the domestication of wild plants that are already tolerant to harsh conditions and to increase their yields by methods such as gene editing. We foresee that crops' wild progenitors could potentially compete with the resulting de novo domesticated plants, reducing yields. To improve the recognition of weeds, we propose using gene editing techniques to introduce traits into de novo domesticated crops that will allow for visual recognition of the crops by weeding robots that have been trained by machine learning.
PubMed: 38637173
DOI: 10.1016/j.tplants.2024.03.001 -
CMAJ : Canadian Medical Association... Mar 2024
Topics: Humans; Continuous Glucose Monitoring; Blood Glucose Self-Monitoring; Blood Glucose
PubMed: 38467414
DOI: 10.1503/cmaj.230572-f -
Frontiers in Microbiology 2024In eukaryotic cells, purine metabolism is the way to the production of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and plays key roles in various biological... (Review)
Review
In eukaryotic cells, purine metabolism is the way to the production of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and plays key roles in various biological processes. Purine metabolism mainly consists of , salvage, and catabolic pathways, and some components of these pathways have been characterized in some plant pathogenic fungi, such as the rice blast fungus and wheat head blight fungus . The enzymatic steps of the pathway are well-conserved in plant pathogenic fungi and play crucial roles in fungal growth and development. Blocking this pathway inhibits the formation of penetration structures and invasive growth, making it essential for plant infection by pathogenic fungi. The salvage pathway is likely indispensable but requires exogenous purines, implying that purine transporters are functional in these fungi. The catabolic pathway balances purine nucleotides and may have a conserved stage-specific role in pathogenic fungi. The significant difference of the catabolic pathway and lead us to further explore and identify the key genes specifically regulating pathogenicity in purine metabolic pathway. In this review, we summarized recent advances in the studies of purine metabolism, focusing on the regulation of pathogenesis and growth in plant pathogenic fungi.
PubMed: 38384269
DOI: 10.3389/fmicb.2024.1352354 -
International Journal of Biological... Jul 2023Patients with Alzheimer's disease (AD) display both peripheral tissue and brain insulin resistance, the later could be a potential risk factor for cognitive dysfunction.... (Review)
Review
Patients with Alzheimer's disease (AD) display both peripheral tissue and brain insulin resistance, the later could be a potential risk factor for cognitive dysfunction. While certain degree of inflammation is required for inducing insulin resistance, underlying mechanism(s) remains unclear. Evidence from diverse research domains suggest that elevated intracellular fatty acids of de novo pathway can induce insulin resistance even without triggering inflammation; however, the effect of saturated fatty acids (SFAs) could be detrimental due the development of proinflammatory cues. In this context, evidence suggest that while lipid/fatty acid accumulation is a characteristic feature of brain pathology in AD, dysregulated de novo lipogenesis could be a potential source for lipid/fatty acid accumulation. Therefore, therapies aimed at regulating de novo lipogenesis could be effective in improving insulin sensitivity and cognitive function in patients with AD.
Topics: Humans; Insulin Resistance; Lipogenesis; Liver; Alzheimer Disease; Fatty Acids; Inflammation
PubMed: 37187418
DOI: 10.1016/j.ijbiomac.2023.124859