Community-based management of arterial hypertension and cardiovascular risk factors by lay village health workers for people with controlled and uncontrolled blood pressure in rural Lesotho: joint protocol for two cluster-randomized trials within the ComBaCaL cohort study (ComBaCaL aHT Twic 1 and ComBaCaL aHT TwiC 2).

BACKGROUND: Arterial hypertension (aHT) is a major cause for premature morbidity and mortality. Control rates remain poor, especially in low- and middle-income countries. Task-shifting to lay village health workers (VHWs) and the use of digital clinical decision support systems may help to overcome the current aHT care cascade gaps. However, evidence on the effectiveness of comprehensive VHW-led aHT care models, in which VHWs provide antihypertensive drug treatment and manage cardiovascular risk factors is scarce. METHODS: Using the trials within the cohort (TwiCs) design, we are assessing the effectiveness of VHW-led aHT and cardiovascular risk management in two 1:1 cluster-randomized trials nested within the Community-Based chronic disease Care Lesotho (ComBaCaL) cohort study (NCT05596773). The ComBaCaL cohort study is maintained by trained VHWs and includes the consenting inhabitants of 103 randomly selected villages in rural Lesotho. After community-based aHT screening, adult, non-pregnant ComBaCaL cohort participants with uncontrolled aHT (blood pressure (BP) ≥ 140/90 mmHg) are enrolled in the aHT TwiC 1 and those with controlled aHT (BP < 140/90 mmHg) in the aHT TwiC 2. In intervention villages, VHWs offer lifestyle counseling, basic guideline-directed antihypertensive, lipid-lowering, and antiplatelet treatment supported by a tablet-based decision support application to eligible participants. In control villages, participants are referred to a health facility for therapeutic management. The primary endpoint for both TwiCs is the proportion of participants with controlled BP levels (< 140/90 mmHg) 12 months after enrolment. We hypothesize that the intervention is superior regarding BP control rates in participants with uncontrolled BP (aHT TwiC 1) and non-inferior in participants with controlled BP at baseline (aHT TwiC 2). DISCUSSION: The TwiCs were launched on September 08, 2023. On May 20, 2024, 697 and 750 participants were enrolled in TwiC 1 and TwiC 2. To our knowledge, these TwiCs are the first trials to assess task-shifting of aHT care to VHWs at the community level, including the prescription of basic antihypertensive, lipid-lowering, and antiplatelet medication in Africa. The ComBaCaL cohort and nested TwiCs are operating within the routine VHW program and countries with similar community health worker programs may benefit from the findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05684055. Registered on January 04, 2023.

Proteomic profiling of Arabidopsis G-protein ß subunit AGB1 mutant under salt stress.

Salt stress is a limiting environmental factor that inhibits plant growth in most ecological environments. The functioning of G-proteins and activated downstream signaling during salt stress is well established and different G-protein subunits and a few downstream effectors have been identified. Arabidopsis G-protein ß-subunit (AGB1) regulates the movement of Na+ from roots to shoots along with a significant role in controlling Na+ fluxes in roots, however, the molecular mechanism of AGB1 mediated salt stress regulation is not well understood. Here, we report the comparative proteome profiles of Arabidopsis AGB1 null mutant agb1-2 to investigate how the absence of AGB1 modulates the protein repertoire in response to salt stress. High-resolution two-dimensional gel electrophoresis (2-DE) showed 27 protein spots that were differentially modulated between the control and NaCl treated agb1-2 seedlings of which seven were identified by mass spectrometry. Functional annotation and interactome analysis indicated that the salt-responsive proteins were majorly associated with cellulose synthesis, structural maintenance of chromosomes, DNA replication/repair, organellar RNA editing and indole glucosinolate biosynthesis. Further exploration of the functioning of these proteins could serve as a potential stepping stone for dissection of molecular mechanism of AGB1 functions during salt stress and in long run could be extrapolated to crop plants for salinity stress management.

Dynamics of virological and immunological markers of HIV persistence after allogeneic haematopoietic stem-cell transplantation in the IciStem cohort: a prospective observational cohort study.

BACKGROUND: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In this study, we aimed to describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT. METHODS: In this prospective observational cohort study, we analysed the viral reservoir and serological dynamics in IciStem cohort participants with HIV who had undergone allo-HSCT and were receiving antiretroviral therapy, ten of whom had received cells from donors with the CCR5Δ32 mutation. Participants from Belgium, Canada, Germany, Italy, the Netherlands, Spain, Switzerland, and the UK were included in the cohort both prospectively and retrospectively between June 1, 2014 and April 30, 2019. In the first 6 months after allo-HSCT, participants had monthly assessments, with annual assessments thereafter, with the protocol tailored to accommodate for the individual health status of each participant. HIV reservoirs were measured in blood and tissues and HIV-specific antibodies were measured in plasma. We used the Wilcoxon signed-rank test to compare data collected before and after allo-HSCT in participants for whom longitudinal data were available. When the paired test was not possible, we used the Mann-Whitney U test. We developed a mathematical model to study the factors influencing HIV reservoir reduction in people with HIV after allo-HSCT. FINDINGS: We included 30 people with HIV with haematological malignancies who received a transplant between Sept 1, 2009 and April 30, 2019 and were enrolled within the IciStem cohort and included in this analysis. HIV reservoirs in peripheral blood were reduced immediately after full donor chimerism was achieved, generally accompanied by undetectable HIV-DNA in bone marrow, ileum, lymph nodes, and cerebrospinal fluid, regardless of donor CCR5 genotype. HIV-specific antibody levels and functionality values declined more slowly than direct HIV reservoir values, decaying significantly only months after full donor chimerism. Mathematical modelling suggests that allogeneic immunity mediated by donor cells is the main viral reservoir depletion mechanism after massive reservoir reduction during conditioning chemotherapy before allo-HSCT (half-life of latently infected replication-competent cells decreased from 44 months to 1·5 months). INTERPRETATION: Our work provides, for the first time, data on the effects of allo-HSCT in the context of HIV infection. Additionally, we raise the question of which marker can serve as the last reporter of the residual viraemia, postulating that the absence of T-cell immune responses might be a more reliable marker than antibody decline after allo-HSCT. FUNDING: amfAR (American Foundation for AIDS Research; ARCHE Program), National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Dutch Aidsfonds.

Metabolomics-driven investigation of plant defense response against pest and pathogen attack.

The advancement of metabolomics has assisted in the identification of various bewildering characteristics of the biological system. Metabolomics is a standard approach, facilitating crucial aspects of system biology with absolute quantification of metabolites using minimum samples, based on liquid/gas chromatography, mass spectrometry and nuclear magnetic resonance. The metabolome profiling has narrowed the wide gaps of missing information and has enhanced the understanding of a wide spectrum of plant-environment interactions by highlighting the complex pathways regulating biochemical reactions and cellular physiology under a particular set of conditions. This high throughput technique also plays a prominent role in combined analyses of plant metabolomics and other omics datasets. Plant metabolomics has opened a wide paradigm of opportunities for developing stress-tolerant plants, ensuring better food quality and quantity. However, despite advantageous methods and databases, the technique has a few limitations, such as ineffective 3D capturing of metabolites, low comprehensiveness, and lack of cell-based sampling. In the future, an expansion of plant-pathogen and plant-pest response towards the metabolite architecture is necessary to understand the intricacies of plant defence against invaders, elucidation of metabolic pathway operational during defence and developing a direct correlation between metabolites and biotic stresses. Our aim is to provide an overview of metabolomics and its utilities for the identification of biomarkers or key metabolites associated with biotic stress, devising improved diagnostic methods to efficiently assess pest and pathogen attack and generating improved crop varieties with the help of combined application of analytical and molecular tools.

Prevalence and predictors of restless legs syndrome among patients having stable chronic obstructive pulmonary disease.

BACKGROUND: Patients having COPD share some factors, e.g., chronic hypoxemia, anemia of chronic disease and nicotine use, which are also the risk factors for RLS hence predispose them to experience RLS in higher then general population. There are limited studies with methodological constraints evaluating the prevalence and/or correlates of RLS among patients with COPD. METHODS: Consecutive adult patients of either gender, having stable COPD as per GOLD guidelines 2021, were assessed for RLS using IRLSSG (2014) criteria (excluding RLS mimics) and the severity of RLS was determined in participants having RLS. Phenomenology of RLS, past medical history and laboratory parameters were gathered. Insomnia and depression were assessed using the insomnia severity index and PHQ-9, respectively. RESULTS: Participants' (N = 210) mean age was 63.02 ± 8.19 years, and 83.8% of subjects were men. 12.9% of participants were found to have RLS. Among those having RLS, nearly half (51.9%) had moderate symptoms, and 18.5% experienced severe symptoms. RLS was more prevalent among younger, females, those having severe COPD, participants having exacerbation of COPD in the previous year, lower post-bronchodilator FEV1, higher dyspnea and COPD assessment test score. Multivariate analysis showed that younger age, female gender, lower post-bronchodilator FEV1, lower FEV1/FVC ratio and higher serum creatinine increased the odds of having RLS. Depressive symptoms were more frequent in participants having RLS. CONCLUSIONS: The present study found that the prevalence of RLS among patients with stable COPD was higher than the general population. Female gender, younger age, higher airflow limitation and higher serum creatinine (though in the physiological range) increase the odds of having RLS. Stable patients with COPD having these characteristics must be screened for RLS.

Evaluation of Hepatic Steatosis and Fibrosis Using Transient Elastography in Patients With Obstructive Sleep Apnea.

Objectives: Obstructive sleep apnea (OSA) is an independent risk factor for non-alcoholic fatty liver disease. This study was planned to assess proportion of patients with OSA that have hepatic steatosis and fibrosis, as measured by transient elastography, to explore variables influencing their development and to find out the polysomnography parameters that predict the need for transient elastography screening in OSA. Methods: Consecutive participants having polysomnography proven OSA were included in the study after screening for eligibility criteria. Data of the polysomnography were scored manually following standard criteria. Participants were subjected to transient elastography (Fibroscan®) and serum investigations after diagnostic polysomnography. The polysomnography, fibroscan®, and laboratory data were tabulated and analyzed. Results: A total of 71 participants were enrolled. 16.9% participants had mild OSA, 28.2% had moderate OSA, and remaining participants had severe OSA. Liver steatosis was found in 63.4% participants while hepatic fibrosis was noted in 9.9%. Oxygen desaturation index (ODI), apnea-hypopnea index (AHI), and percentage of sleep spent below 90% oxygen saturation (T90) were significantly associated with the presence of hepatic steatosis and fibrosis. Receiver operating curve (ROC) showed that at the cut-offs of 73 events/hr, 13% and 72.2 events/hr, AHI, T90 and ODI, predicted hepatic fibrosis with area under ROC of 0.960, 0.944, and 0.933, respectively (P < 0.001). Conclusions: Patients with OSA are at increased risk for development of hepatic steatosis and fibrosis. ODI, AHI, and T90 during polysomnography predict the presence of underlying hepatic fibrosis.

Comparison of prior authorization across insurers: cross sectional evidence from Medicare Advantage.

OBJECTIVE: To measure and compare the scope of US insurers' policies for prior authorization (PA), a process by which insurers assess the necessity of planned medical care, and to quantify differences in PA across insurers, physician specialties, and clinical service categories. DESIGN: Cross sectional analysis. SETTING: PA policies for five insurers serving most of the beneficiaries covered by privately administered Medicare Advantage in the US, 2021, as applied to utilization patterns observed in Medicare Part B. PARTICIPANTS: 30 540 086 beneficiaries in traditional Medicare Part B. MAIN OUTCOME MEASURES: Proportions of government administered traditional Medicare Part B spending and utilization that would have required PA according to Medicare Advantage insurer rules. RESULTS: The insurers required PA for 944 to 2971 of the 14 130 clinical services (median 1899; weighted mean 1429) constituting 17% to 33% of Part B spending (median 28%; weighted mean 23%) and 9% to 41% of Part B utilization (median 22%; weighted mean 18%). 40% of spending ($57bn; £45bn; €53bn) and 48% of service utilization would have required PA by at least one insurer; 12% of spending and 6% of utilization would have required PA by all insurers. 93% of Part B medication spending, or 74% of medication use, would have required PA by at least one Medicare Advantage insurer. For all Medicare Advantage insurers, hematology and oncology drugs represented the largest proportion of PA spending (range 27-34%; median 33%; weighted mean 30%). PA rates varied widely across specialties. CONCLUSION: PA policies varied substantially across private insurers in the US. Despite limited consensus, all insurers required PA extensively, particularly for physician administered medications. These findings indicate substantial differences in coverage policies between government administered and privately administered Medicare. The results may inform ongoing efforts to focus PA more effectively on low value services and reduce administrative burdens for clinicians and patients.

Evolution of reactive oxygen species cellular targets for plant development.

Reactive oxygen species (ROS) are the key players in regulating developmental processes of plants. Plants have evolved a large array of gene families to facilitate the ROS-regulated developmental process in roots and leaves. However, the cellular targets of ROS during plant evolutionary development are still elusive. Here, we found early evolution and large expansions of protein families such as mitogen-activated protein kinases (MAPK) in the evolutionarily important plant lineages. We review the recent advances in interactions among ROS, phytohormones, gasotransmitters, and protein kinases. We propose that these signaling molecules act in concert to maintain cellular ROS homeostasis in developmental processes of root and leaf to ensure the fine-tuning of plant growth for better adaptation to the changing climate.

Generative Artificial Intelligence to Transform Inpatient Discharge Summaries to Patient-Friendly Language and Format.

Importance: By law, patients have immediate access to discharge notes in their medical records. Technical language and abbreviations make notes difficult to read and understand for a typical patient. Large language models (LLMs [eg, GPT-4]) have the potential to transform these notes into patient-friendly language and format. Objective: To determine whether an LLM can transform discharge summaries into a format that is more readable and understandable. Design, Setting, and Participants: This cross-sectional study evaluated a sample of the discharge summaries of adult patients discharged from the General Internal Medicine service at NYU (New York University) Langone Health from June 1 to 30, 2023. Patients discharged as deceased were excluded. All discharge summaries were processed by the LLM between July 26 and August 5, 2023. Interventions: A secure Health Insurance Portability and Accountability Act-compliant platform, Microsoft Azure OpenAI, was used to transform these discharge summaries into a patient-friendly format between July 26 and August 5, 2023. Main Outcomes and Measures: Outcomes included readability as measured by Flesch-Kincaid Grade Level and understandability using Patient Education Materials Assessment Tool (PEMAT) scores. Readability and understandability of the original discharge summaries were compared with the transformed, patient-friendly discharge summaries created through the LLM. As balancing metrics, accuracy and completeness of the patient-friendly version were measured. Results: Discharge summaries of 50 patients (31 female [62.0%] and 19 male [38.0%]) were included. The median patient age was 65.5 (IQR, 59.0-77.5) years. Mean (SD) Flesch-Kincaid Grade Level was significantly lower in the patient-friendly discharge summaries (6.2 [0.5] vs 11.0 [1.5]; P < .001). PEMAT understandability scores were significantly higher for patient-friendly discharge summaries (81% vs 13%; P < .001). Two physicians reviewed each patient-friendly discharge summary for accuracy on a 6-point scale, with 54 of 100 reviews (54.0%) giving the best possible rating of 6. Summaries were rated entirely complete in 56 reviews (56.0%). Eighteen reviews noted safety concerns, mostly involving omissions, but also several inaccurate statements (termed hallucinations). Conclusions and Relevance: The findings of this cross-sectional study of 50 discharge summaries suggest that LLMs can be used to translate discharge summaries into patient-friendly language and formats that are significantly more readable and understandable than discharge summaries as they appear in electronic health records. However, implementation will require improvements in accuracy, completeness, and safety. Given the safety concerns, initial implementation will require physician review.

Comparative evaluation of antioxidant activity, total phenolic content, anti-inflammatory, and antibacterial potential of Euphorbia-derived functional products.

This study assessed the medicinal properties of Euphorbia resinifera O. Berg (E. resinifera) and Euphorbia officinarum subsp echinus (Hook.f. and Coss.) Vindt (Euphorbia echinus, known for their pharmaceutical benefits. Extracts from their flowers, stems, propolis, and honey were examined for phenolic content, antioxidant, anti-inflammatory, and antibacterial activities. Total phenolic content (TPC), total flavonoid content (TFC), and total condensed tannin (TCC) were determined using specific methods. Antioxidant potential was assessed through various tests including DPPH, FRAP, ABTS, and Total antioxidant capacity. Anti-inflammatory effects were evaluated using phenol-induced ear edema in rats, while antibacterial activity was measured against Gram-positive (Staphylococcus aureus ATCC 6538) and Gram-negative (E. coli ATCC 10536) bacteria. Among the extracts, the aqueous propolis extract of E. resinifera demonstrated exceptional antioxidant capabilities, with low IC50 values for DPPH (0.07 ± 0.00 mg/mL) and ABTS (0.13 ± 0.00 mg/mL), as well as high TAC (176.72 ± 0.18 mg AA/mg extract) and FRAP (86.45 ± 1.45 mg AA/mg extract) values. Furthermore, the anti-inflammatory effect of E. resinifera propolis extracts surpassed that of indomethacin, yielding edema percentages of 3.92% and 11.33% for the aqueous and ethanolic extracts, respectively. Microbiological results indicated that the aqueous extract of E. resinifera flower exhibited the most potent inhibitory action against S. aureus, with an inhibition zone diameter (IZD) of 21.0 ± 0.00 mm and a minimum inhibitory concentration (MIC) of 3.125 mg/mL. Additionally, only E. resinifera honey displayed the ability to inhibit E. coli growth, with an inhibition zone diameter of 09.30 ± 0.03 mm and a MIC of 0.0433 mg/mL.

Randomized Experiments to Reduce Overuse of Health Care: A Scoping Review.

OBJECTIVE: Health care overuse is pervasive in countries with advanced health care delivery systems. We hypothesize that effective interventions to reduce low-value care that targets patients or clinicians are mediated by psychological and cognitive processes that change behaviors and that interventions targeting these processes are varied. Thus, we performed a scoping review of experimental studies of interventions, including the interventions' objectives and characteristics, to reduce low-value care that targeted psychological and cognitive processes. METHODS: We systematically searched databases for experimental studies of interventions to change cognitive orientations and affective states in the setting of health care overuse. Outcomes included observed overuse or a stated intention to use services. We used existing frameworks for behavior change and mechanisms of change to categorize the interventions and the mediating processes. RESULTS: Twenty-seven articles met the inclusion criteria. Sixteen studied the provision of information to patients or clinicians, with most providing cost information. Six studies used educational interventions, including the provision of feedback about individual practice. Studies rarely used counseling, behavioral nudges, persuasion, and rewards. Mechanisms for behavior change included gain in knowledge or confidence and motivation by social norms. CONCLUSIONS: In this scoping review, we found few experiments testing interventions that directly target the psychological and cognitive processes of patients or clinicians to reduce low-value care. Most studies provided information to patients or clinicians without measuring or considering mediating factors toward behavior change. These findings highlight the need for process-driven experimental designs, including trials of behavioral nudges and persuasive language involving a trusting patient-clinician relationship, to identify effective interventions to reduce low-value care.

Sleep quality and obstructive sleep apnea among male patients with lower urinary tract symptoms: A prospective observational study.

Introduction: Apart from nocturia, few reports have been published on the relationship between lower urinary tract symptoms (LUTS) and sleep disturbances in patients visiting urology outpatient clinics. This study assessed the association between our population's LUTS and sleep disturbances. Methods: This was a prospective observational study. A total of 123 male patients with a history of LUTS aged more than 40 years were recruited from urology outpatient clinic. International Prostate Symptom Score was utilized to assess LUTS. To determine the quality of sleep, the Pittsburgh Sleep Quality Index (PSQI) was used. Berlin questionnaire (BQ) was used for screening obstructive sleep apnea. Results: A total of 123 participants were enrolled in this study. The mean age of the participants was 61 ± 11.1 years. Nocturia >3 episodes were significantly more in patients with PSQI >5 (P < 0.05). There was a greater prevalence of severe LUTS in patients with PSQI >5 (P < 0.05). The association between LUTS and BQ score showed an increased prevalence of severe symptoms in patients with high BQ. Patients with PSQI >5 had more severe LUTS (53% of patients) compared to patients with PSQI ≤5 (5% of patients) (P = 0.000). Patients with PSQI >5 had overall poorer quality of life (QOL) scores, with QOL being 5 and 6 in 18% and 4.8% of the patients, respectively. Conclusions: There is a significant association between the prevalence of nocturia, moderate-to-severe LUTS, and the existence of sleep disorders. Therefore, screening for sleep disturbances may be performed on male patients who present with LUTS.

Methyl-salicylate: A surveillance system for triggering immunity in neighboring plants.

After being infested by aphids, plants trigger a signaling pathway that involves methyl salicylate as an airborne signaling molecule. Thus, the regulation of communication for systemically acquired resistance produced via methyl salicylate is helpful in generating stress resistance among plants against aphid infestation.

Published research on the human health implications of climate change between 2012 and 2021: cross sectional study.

Objective: To better understand the state of research on the effects of climate change on human health, including exposures, health conditions, populations, areas of the world studied, funding sources, and publication characteristics, with a focus on topics that are relevant for populations at risk. Design: Cross sectional study. Data sources: The National Institute of Environmental Health Sciences climate change and human health literature portal, a curated bibliographical database of global peer reviewed research and grey literature was searched. The database combines searches of multiple search engines including PubMed, Web of Science, and Google Scholar, and includes added-value expert tagging of climate change exposures and health impacts. Eligibility criteria: Inclusion criteria were peer reviewed, original research articles that investigated the health effects of climate change and were published in English from 2012 to 2021. After identification, a 10% random sample was selected to manually perform a detailed characterisation of research topics and publication information. Results: 10 325 original research articles were published between 2012 and 2021, and the number of articles increased by 23% annually. In a random sample of 1014 articles, several gaps were found in research topics that are particularly relevant to populations at risk, such as those in the global south (134 countries established through the United Nations Office for South-South Cooperation) (n=444; 43.8%), adults aged 65 years or older (n=195; 19.2%), and on topics related to human conflict and migration (n=25; 2.5%) and food and water quality and security (n=148; 14.6%). Additionally, fewer first authors were from the global south (n=349; 34.4%), which may partly explain why research focusing on these countries is disproportionally less. Conclusions: Although the body of research on the health effects of climate change has grown substantially over the past decade, including those with a focus on the global south, a disproportionate focus continues to be on countries in the global north and less at risk populations. Governments are the largest source of funding for such research, and governments, particularly in the global north, need to re-orient their climate and health research funding to support researchers in the global south and to be more inclusive of issues that are relevant to the global south.

Temporally-coordinated bivalent histone modifications of BCG1 enable fungal invasion and immune evasion.

Bivalent histone modifications, including functionally opposite H3K4me3 and H3K27me3 marks simultaneously on the same nucleosome, control various cellular processes by fine-tuning the gene expression in eukaryotes. However, the role of bivalent histone modifications in fungal virulence remains elusive. By mapping the genome-wide landscape of H3K4me3 and H3K27me3 dynamic modifications in Fusarium graminearum (Fg) during invasion, we identify the infection-related bivalent chromatin-marked genes (BCGs). BCG1 gene, which encodes a secreted Fusarium-specific xylanase containing a G/Q-rich motif, displays the highest increase of bivalent modification during Fg infection. We report that the G/Q-rich motif of BCG1 is a stimulator of its xylanase activity and is essential for the full virulence of Fg. Intriguingly, this G/Q-rich motif is recognized by pattern-recognition receptors to trigger plant immunity. We discover that Fg employs H3K4me3 modification to induce BCG1 expression required for host cell wall degradation. After breaching the cell wall barrier, this active chromatin state is reset to bivalency by co-modifying with H3K27me3, which enables epigenetic silencing of BCG1 to escape from host immune surveillance. Collectively, our study highlights how fungal pathogens deploy bivalent epigenetic modification to achieve temporally-coordinated activation and suppression of a critical fungal gene, thereby facilitating successful infection and host immune evasion.

Integrated "-omics" analysis highlights the role of brassinosteroid signaling and antioxidant machinery underlying improved rice seed longevity during artificial aging treatment.

Seed longevity is a critical characteristic in agriculture, yet the specific genes/proteins responsible for this trait and the molecular mechanisms underlying reduced longevity during seed aging remain largely elusive. Here we report the comparative proteome and metabolome profiling of three rice cultivars exhibiting varying degrees of aging tolerance: Dharial, an aging-tolerant cultivar; Ilmi, an aging-sensitive cultivar; and A2, a moderately aging-tolerant cultivar developed from the crossbreeding of Dharial and Ilmi. Artificial aging treatment (AAT) markedly reduced the germination percentage and enhanced the activities of antioxidant enzymes in all the cultivars. Further, proteomics results showed a key role of the ubiquitin (Ub)-proteasome pathway in the degradation of damaged proteins during AAT while other proteases were majorly reduced. In addition, proteins associated with energy production and protein synthesis were strongly reduced in Ilmi while these were majorly increased in A2 and Dharial. These, along with metabolomics results, suggest that Ub-proteasome mediated protein degradation during AAT results in the accumulation of free amino acids in Ilmi while tolerant cultivars potentially utilize those for energy production and synthesis of stress-related proteins, especially hsp20/alpha-crystallin family protein. Additionally, both Dharial and A2 seem to activate brassinosteroid signaling and suppress jasmonate signaling which initiates a signaling cascade that allows accumulation of enzymatic and non-enzymatic antioxidants for efficient detoxification of aging-induced ROS. Taken together, these results provide an in-depth understanding of the aging-induced changes in rice seeds and highlight key pathways responsible for maintaining seed longevity during AAT.