Timing Of Events Research Articles

Sequestration of gene products by decoys enhances precision in the timing of intracellular events

Expressed gene products often interact ubiquitously with binding sites at nucleic acids and macromolecular complexes, known as decoys. The binding of transcription factors (TFs) to decoys can be crucial in controlling the stochastic dynamics of gene expression. Here, we explore the impact of decoys on the timing of intracellular events, as captured by the time taken for the levels of a given TF to reach a critical threshold level, known as the first passage time (FPT). Although nonlinearity introduced by binding makes exact mathematical analysis challenging, employing suitable approximations and reformulating FPT in terms of an alternative variable, we analytically assess the impact of decoys. The stability of the decoy-bound TFs against degradation impacts FPT statistics crucially. Decoys reduce noise in FPT, and stable decoy-bound TFs offer greater timing precision with less expression cost than their unstable counterparts. Interestingly, when both bound and free TFs decay at the same rate, decoy binding does not directly alter FPT noise. We verify these results by performing exact stochastic simulations. These results have important implications for the precise temporal scheduling of events involved in the functioning of biomolecular clocks, development processes, cell-cycle control, and cell-size homeostasis.

Comprehensive phylogenomic analysis of Zika virus: Insights into its origin, past evolutionary dynamics, and global spread

BackgroundZika virus (ZIKV), a Flaviviridae family member, has been linked to severe neurological disorders. Despite detailed studies on recent outbreaks, the early evolutionary history of ZIKV remains partially unclear. This study elucidates ZIKV origin and evolutionary dynamics, focusing on recombination events, early lineage diversification, and virus spread across continents. MethodsWe assessed recombination using multiple methods. We conducted Bayesian phylogenetic analyses to understand the evolutionary relationships and timing of key diversification events. Model selection was carried out to determine the most appropriate evolutionary model for our dataset. ResultsOur phylogenies revealed recent recombination between Singaporean and African lineages, indicating the co-circulation of diverse lineages during outbreaks. Thailand was identified as a crucial hub in the spread across Asia. The phylogenetic analysis suggests that the ZIKV lineage dates back to the eleventh century, with the first significant diversification occurring in the nineteenth century. The timing of the re-introduction of the Asian lineage into Africa and the delay between probable introduction and outbreak onset were also determined. ConclusionsThis study provides novel insights into ZIKV's origin and early evolutionary dynamics, highlighting Thailand's role in the spread of the virus in Asia and recent recombination events between distant lineages. These findings emphasize the need for continuous surveillance and a better understanding of ZIKV biology to forecast and mitigate future outbreaks.

Expected First Occurrence Time of Uncertain Future Events in One-Dimensional Linear Systems

The rapid advancement of machine learning algorithms has significantly enhanced tools for monitoring system health, making data-driven approaches predominant in Prognostics and Health Management (PHM). In contrast, model-based approaches have seen modest progress, as they are often constrained by the need for prior knowledge of specific governing equations, limiting their applicability to a wide range of problems. Recently, rigorous theoretical foundations have been established to extend dynamical systems theory by incorporating prognosis of uncertain events. This article leverages this formal framework to introduce and demonstrate a fundamental mathematical result for one-dimensional linear dynamical systems. The presented theorem offers an exact expression for calculating the expected time at which an event will first occur in the future. Unlike typical thresholds, this event is triggered by a hazard zone, defined as an uncertain event likelihood function over the system's state space. Applications of this theorem can be found in implementing real-time prognostic frameworks, where it is crucial to quickly estimate the magnitude of impending failures. Emphasis is placed on minimizing computational burden to facilitate prognostic decision-making.

Center of mass kinematic reconstruction during steady-state walking using optimized template models.

Template models, such as the Bipedal Spring-Loaded Inverted Pendulum and the Virtual Pivot Point, have been widely used as low-dimensional representations of the complex dynamics in legged locomotion. Despite their ability to qualitatively match human walking characteristics like M-shaped ground reaction force (GRF) profiles, they often exhibit discrepancies when compared to experimental data, notably in overestimating vertical center of mass (CoM) displacement and underestimating gait event timings (touchdown/ liftoff). This paper hypothesizes that the constant leg stiffness of these models explains the majority of these discrepancies. The study systematically investigates the impact of stiffness variations on the fidelity of model fittings to human data, where an optimization framework is employed to identify optimal leg stiffness trajectories. The study also quantifies the effects of stiffness variations on salient characteristics of human walking (GRF profiles and gait event timing). The optimization framework was applied to 24 subjects walking at 40% to 145% preferred walking speed (PWS). The findings reveal that despite only modifying ground forces in one direction, variable leg stiffness models exhibited a >80% reduction in CoM error across both the B-SLIP and VPP models, while also improving prediction of human GRF profiles. However, the accuracy of gait event timing did not consistently show improvement across all conditions. The resulting stiffness profiles mimic walking characteristics of ankle push-off during double support and reduced CoM vaulting during single support.

Species Diversity, Host Association, and Evolutionary History of Cronartium: An Important Global Fungal Pathogen to Trees

ABSTRACTPine stem rust, the most damaging and widespread forest disease occurring in pine trees in the Northern Hemisphere, is primarily caused by Cronartium species (Pucciniales, Melampsorineae). While the phylogenetic relationships of major Cronartium species have been largely elucidated, there is limited understanding of their species diversity and the evolutionary processes shaping their distribution patterns. In this work, we performed broad sampling and sequencing of Cronartium taxa in China together with additional sequence data and other accessions in NCBI to investigate the diversification and to estimate the divergence time of major evolutionary events in this genus. Molecular dating analysis suggested that the divergence of the genus Cronartium probably was around 91.78 Ma during the Upper Cretaceous. It is believed that Cronartium species may have originated in Asia and North America, with intercontinental dispersals occurring primarily during the Middle Eocene, Middle Miocene, and Pliocene. These dispersal events likely took place through the North Atlantic Land Bridge, the De Geer Route, and the Bering Land Bridge, and subsequently diverged through sporadic dispersal and vicariance events. Furthermore, our analysis of host associations revealed that the diversification of Cronartium species was correlated with their telial‐hosts, and some species may have experienced host jump events, indicating a complex interplay between host specificity and pathogen–host interaction during Cronartium evolution.

Greening‐Induced Biophysical Impacts Lead to Earlier Spring and Autumn Phenology in Temperate and Boreal Forests

AbstractTree phenology, the timing of periodic biological events in trees, is highly sensitive to climate change. Previous studies have indicated that forest greening can impact the local climate by modifying the seasonal surface energy budget. However, the understanding of tree phenological responses to forest greening at large spatial scales remains limited. Utilizing satellite‐derived phenological and leaf area index data spanning from 2001 to 2021, herein we show that forest greening led to earlier spring and autumn phenology in both temperate and boreal forests. Our findings demonstrated that forest greening during winter and spring contributed to a reduction in surface albedo, resulting in biophysical warming and consequently advancing spring leaf phenology. Conversely, forest greening in summer and autumn induced biophysical cooling through increased evapotranspiration, leading to an earlier onset of autumn leaf phenology. Our findings highlight the significant impact of forest greening‐induced local seasonal climate changes on shaping tree phenology in temperate and boreal forests. It is crucial to consider these greening‐induced alterations in microclimate conditions when modeling changes in tree phenology under future climate warming scenarios.

Asymptotic normality of a relative error functional regression estimator under left truncation and right censoring

. In this article, we introduce a non parametric regression estimator based on a relative error criterion, for left truncated and right censored data with functional predictors. Left truncation and right censoring are common forms of incomplete data in survival analysis, where the event time of interest is only observed within a certain interval which adds some challenges to the regression task. We establish the asymptotic normality of our estimator and develop a procedure for constructing confidence intervals for the predicted responses. The theoretical results obtained are supported using simulation studies and a real data example from the energy field.

Characterization, outcomes and time to event predictors of urinary tract infections acquired during post-acute stroke inpatient rehabilitation: A comprehensive cohort study

ObjectivesTo i) compare baseline clinical and demographic characteristics of post-acute stroke inpatients who were diagnosed with first-time urinary tract infection (UTI) vs inpatients who were not ii) compare rehabilitation outcomes between both groups and iii) examine associations between time to UTI event and risk factors. DesignRetrospective observational cohort study SettingInstitution for inpatient neurological rehabilitation. ParticipantsInpatients (n=1683) admitted within 3 months post-stroke to a rehabilitation facility between 2005 and 2023. InterventionsNot applicable. Main Outcome MeasuresFunctional Independence Measure (FIM), Functional Ambulation Categories (FAC) at admission. Cox proportional hazards models analyzed the association between UTI event timing and risk factors. ResultsOf the (n=1683) included patients, 196 (11.6%) experienced a UTI. In 32.1% of cases, the UTI occurred during the first week after admission to rehabilitation and 47.9% of UTIs occurred during the first two weeks. Median (IQR) time to UTI was 16 (5-37) days since admission. Most common germs were Escherichia coli (40.5%), Klebsiella pneumoniae (23.7%) and Pseudomonas aeruginosa (6.4%). Patients who acquired a UTI had older age, higher stroke severity, higher proportion of dysphagia, hypertension, neglect, bilateral affectation, atrial fibrillation, hemiplegia, lower levels of functional independence and lower FAC. We identified no differences in sex, type of stroke (ischemic or hemorrhagic), time to admission, aphasia, diabetes, dyslipidemia, chronic obstructive pulmonary disease, dominant side affected and educational level between both groups. Patients with UTI presented significantly poorer rehabilitation outcomes including lower discharge FIM and FAC, larger LOS, lower FIM efficiency and decreased FIM effectiveness.Multivariable Cox proportional hazards identified hypertension HR=1.60(1.13-2.27), admission FIM HR=0.98(0.97-0.99), admission BMI HR=0.96(0.93-0.99) and admitted with catheter HR= 1.80(1.22-2.64) as significant predictors of time to first UTI event (Concordance-index = 0.754). ConclusionsUTIs identification, characterization, and predictive factors can support post-acute stroke mitigation strategies to minimize UTI-related complications and optimize rehabilitation outcomes.

Carotid plaque thickness predicts cardiovascular events and death in patients with chronic kidney disease

BackgroundClassical risk scoring systems underestimate the risk of cardiovascular disease in chronic kidney disease (CKD). Coronary artery calcium score (CACS) has improved prediction of cardiovascular events in patients with CKD. The maximal carotid plaque thickness (cPTmax) measured in ultrasound scans of the carotid arteries has demonstrated similar predictive value as CACS in the general population. This is the first study to investigate whether cPTmax can predict cardiovascular events in CKD and to compare the predictive value of cPTmax and CACS in CKD.MethodTwo hundred patients with CKD stage 3 from the Copenhagen CKD Cohort underwent ultrasound scanning of the carotid arteries. The assessment consisted of locating plaque and measuring the thickest part of the plaque, cPTmax. Based on the distribution of cPTmax, the participants were divided into 3 groups: No plaques, cPTmax 1.0–1.9 mm and cPTmax > 1.9 mm (median cPTmax = 1.9 mm among patients with plaques). To measure CACS, 175 of the patients underwent a non-contrast CT scan of the coronary arteries. The follow-up time spanned between the ultrasound scan and a predefined end-date or the time of first event, defined as a composite of major cardiovascular events or death of any cause (MACE).ResultsThe median follow-up time was 5.4 years during which 45 patients (22.5%) developed MACE. In a Cox-regression adjusted for classical cardiovascular risk factors, patients with cPTmax > 1.9 mm had a significantly increased hazard ratio of MACE (HR 3.2, CI: 1.1–9.3), p = 0.031) compared to patients without plaques. C-statistics was used to evaluate models for predicting MACE. The improvement in C-statistics was similar for the two models including classical cardiovascular risk factors plus cPTmax (0.247, CI: 0.181–0.312) and CACS (0.243, CI: 0.172–0.315), respectively, when compared to a model only controlled for time since baseline (a Cox model with no covariates).ConclusionOur results indicate that cPTmax may be useful for predicting MACE in CKD. cPTmax and CACS showed similar ability to predict MACE.

Modeling the Bioenergetics and Life History Traits of Chironomus riparius–Consequences of Food Limitation

Chironomids have a number of characteristics that make them a useful group for investigating the impact of environmental and chemical stressors on their life cycle stages. It is crucial to first understand sensitivities to environmental factors and provide a basis for interpreting the results of toxicity tests. We focused on Chironomus riparius–one of the most studied species in aquatic toxicity tests—to understand the changes during the larval stage under conditions of food abundance and limitation. We developed a model based on Dynamic Energy Budget (DEB) theory, a framework to capture the entire life cycle of an individual under varying food and temperature conditions. Available information from this study and the literature pointed out that the first three larval instars are immature and the fourth larval instar is mature, during which the organism saves, in two phases, energy for essential processes occurring during the subsequent non-feeding stages. The model can successfully predict the observed prolonged fourth instar duration under food limitation, the times of life history events (e.g., pupation and emergence), and egg production. This model has the potential to be integrated with toxicokinetic–toxicodynamic models to study the effects of toxicants on a variety of biological traits.

Temporal recording of mammalian development and precancer

Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations1,2, an alternative solution leverages irreversible genetic changes, such as naturally occurring mutations, to create indelible marks that enables retrospective temporal ordering3–5. Using a multipurpose, single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, with incorporation of cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during mouse embryonic development, unconventional developmental relationships between cell types and new epithelial progenitor states by their unique genetic histories. Analysis of mouse adenomas, coupled to multiomic and single-cell profiling of human precancers, with clonal analysis of 418 human polyps, demonstrated the occurrence of polyclonal initiation in 15–30% of colonic precancers, showing their origins from multiple normal founders. Our study presents a multimodal framework that lays the foundation for in vivo recording, integrating synthetic or natural indelible genetic changes with single-cell analyses, to explore the origins and timing of development and tumorigenesis in mammalian systems.

Stress timing, trauma exposure, and family resilience differentially affect internalizing and externalizing symptoms at 3, 5, and 7 years of age

Mental health disorders are associated with decreased quality of life, economic productivity loss, and increased mortality. The association between stressful experiences and psychopathology is well documented. However, studies are needed to understand the impact of timing of stressful events, types of traumatic experiences, and of family resilience on internalizing and externalizing symptoms in early childhood. The present study used a longitudinal design towards this end. Parents (N = 456) completed study measures at infancy, 2 years, 3 years, 5 years, and 7 years. At 3 years, greater stressful events during the prenatal period, 1-2 years, and 2-3 years (B = 0.833–0.369, p = 0.028–0.046) predicted internalizing symptoms for female participants only. For externalizing symptoms at 3 years, every time point assessed was significantly associated with more symptoms across both sexes (B = 1.071–0.414, p < 0.001). At 5 years, both internalizing and externalizing symptoms were associated with a greater number of stressful events at every time point and across sexes (B = 1.372–0.465, p < 0.001–0.002). There was evidence for timing effects, including cumulative effects, sensitive periods, and recency effects. Exposure to interpersonal trauma associated with greater internalizing symptoms (B = 2.120, p = 0.002), whereas both interpersonal (B = 1.879, p = 0.005) and non-interpersonal (B = 1.223, p = 0.032) traumatic experiences were associated with greater externalizing symptoms. Aspects of family resilience including higher levels of family commitment, ability to face challenges, and sense of control reduced risk for internalizing symptoms (B = –0.496, p = 0.004) while only greater sense of control (B = –0.838, p = 0.040) reduced risk for externalizing symptoms at age 7 years, including in the context of trauma.

Prognosis and Risks for Probable Chronic Lung Allograft Dysfunction: A Prospective Multicenter Study.

Chronic lung allograft dysfunction (CLAD) hinders lung transplant success. A 2019 consensus refined CLAD diagnosis, introducing probable or definite CLAD based on persistence of lung function decline. Outcomes and risks for probable CLAD remain uncertain. Determine the prognosis and clinical risks for probable CLAD in a prospective multicenter cohort. Clinical Trials in Organ Transplantation-20 included 745 CLAD-eligible adult lung recipients at 5 centers and applied rigorous methods to prospectively adjudicate probable CLAD. The impact of probable CLAD on graft loss was determined using a Cox model that considered CLAD as a time-dependent covariate. Regularized Cox modeling with LASSO penalty was used to evaluate donor or recipient characteristics and the occurrence and timing of posttransplant events as probable CLAD risks. Similar analyses were performed for definite CLAD. Probable CLAD occurred in 29.7% of patients at 3 years posttransplant and conferred a marked increase in risk for graft loss (unadjusted HR 4.38, p<0.001). Most patients (80%) with probable CLAD progressed to definite CLAD. Cytomegalovirus infection and specifically late presence (>90 days posttransplant) of donor-specific alloantibodies, acute rejection, acute lung injury, or organizing pneumonia contributed the greatest independent information about probable CLAD risk. Definite CLAD risks were similar. Probable CLAD identifies patients at high risk for graft loss, supporting prospective identification of this condition for early initiation of CLAD-directed interventions. More effective strategies to prevent posttransplant cytomegalovirus, inhibit allospecific immunity, and reduce tissue injury are needed to reduce probable CLAD and improve lung recipient survival.

Micro- to nano-sized solid inclusions in magnetite record skarn reactions

Abstract. Magnetite is a widespread ore mineral in skarn systems and usually hosts a wide variety of inclusions. Micro- to nano-sized solid inclusions in magnetite are unique tools to track the evolutionary processes of its host mineral and, subsequently, to constrain the timing of the mineralization event. In this study, we characterize micro- to nano-sized solid inclusions in magnetite from the La Víbora magnesian skarn (Málaga, Spain) using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). TEM energy-dispersive X-ray spectrometry (EDS) analyses and compositional mapping expose two types of nano-inclusions oriented along the (111) of magnetite: type 1 includes dolomite, spinel, and Mg–Fe–Al silicate, and type 2 is made up of Mg–Fe–Al silicates enveloping the Mg-bearing amorphous silica phase. High-resolution transmission electron microscopy (HRTEM), selected-area electron diffraction (SAED), and fast Fourier transform (FFT) patterns reveal that the majority of the solid inclusions display non-oriented matrices compared to the host magnetite, precluding the possibility of sub-solidus processes. Instead, these inclusions are thought to preserve skarn mineral assemblages that were entrapped during the growth of magnetite. However, the local supersaturation of fluids trapped in the boundary layer of crystallizing magnetite is evidenced by coherent lattice orientation of precipitated and host magnetite and by the occurrence of an Mg-bearing amorphous silica phase. Our findings reveal that skarn reactions observed at field and microscopic scales are also recorded in nano-sized inclusions within magnetite. These observations underscore the significance of micro- to nano-scale solid inclusions in magnetite to decipher overprinted skarn reactions as well as constraining the timing of Fe mineralization events in skarns.

High-intensity exercise-related sudden cardiac death in hypertrophy cardiomyopathy

Abstract Background Whether exercise provokes sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM) is uncertain. Current European guidelines recommend against high-intensity exercise in individuals with high SCD risk or obstructive physiology. Purpose We investigated the factors associated with exercise-related SCD in HCM. Methods We retrospectively analyzed of 2,844 consecutive patients with HCM who underwent evaluation between 2005 and 2023 at a high-volume tertiary center. SCD events were defined as a composite of aborted SCD, appropriate implantable cardioverter-defibrillator (ICD) shock, and SCD. Among 80 first SCD events (2.8%), 75 events had a description of the physical activity at the time of the event. Patients were classified into two groups according to physical activity level at the time of the SCD event. Group 1 included patients with high-intensity exercise-related SCD events, defined as happening during or immediately after high-intensity exercise or physical activity, while Group 2 included patients with SCD events happening at rest or during light or moderate physical activity. Results The 75 first SCD events included 44 aborted SCD, 22 appropriate ICD shocks, and 9 SCD. Median age at SCD event was 54 (IQR 39.5–62.5) years and 60 (80%) were men. Patients in Group 1 (n=14) were younger than patients in Group 2 (n=61) (23.5 [IQR 16–48] vs. 55 [IQR 44–64] years, p&amp;lt;0.001), and most patients in group 1 (92.9%) were under the age of 60 years. Patients in Group 1 had slightly smaller left ventricular (LV) end-diastolic dimension and had higher ESC SCD risk scores (3.6 [IQR 2.5–6.7] vs. 2.4 [IQR 1.7–4.8], p=0.044) than patients in Group 2; however, there were no significant differences in the proportion of high-risk patients (28.6% vs. 14.8%, p=0.396) or patients with AHA major SCD risk factors (57.1% vs. 55.7%, p=0.999). Otherwise, there were no significant differences in the presence of obstructive physiology, apical HCM, and apical aneurysm, LV systolic and diastolic function, and comorbidities between the two groups. Furthermore, of the 29 patients who underwent genetic testing, there was no difference in the proportion of patients with pathogenic sarcomeric variants according to exercise-related SCD (50.0% vs. 65.2%, p=0.683). To note, there was a non-significant tendency towards higher proportion of thin filament variants in Group 1 than Group 2 among those with pathogenic sarcomeric variants (100% [3/3] vs 26.7% [4/15], p=0.084). Conclusions Most high-intensity exercise-related SCD events happened under the age of 60. The ESC SCD risk score was higher in patients with high-intensity exercise-related SCD events, although the SCD risk categories or AHA risk factors could not discriminate patients at higher risk of events. These results suggest that exercise recommendations should not be based on SCD risk category, presence of obstruction, or degree of LV hypertrophy.

Smoking cessation after acute myocardial infarction: a Swiss-wide cohort study

Abstract Background Smoking is a major cardiovascular risk factor and of great importance in terms of both primary and secondary prevention. The present study aims to identify patient characteristics associated with smoking cessation within 1 year after acute myocardial infarction (AMI) to inform physician-patient interactions, secondary prevention measures, and public health planning. Methods ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) patients enrolled between 2012 and 2022 in the AMIS Plus registry who were active smokers at the time of the index event were included. At the 1-year follow-up, patients were questioned about their smoking behaviour via telephone interview and were further classified into those who had quit (stoppers) or continued (continuers) smoking. Patient characteristics were collected at the time of the index event and at follow-up and then compared using descriptive statistics. Results From a total of 4523 patients with AMI, 4242 (93.8%) provided information regarding their smoking status at a median follow-up of 395 days (interquartile range 370 to 469) after the index event. Of 1691 (39.9%) active smokers at the time of AMI, 861 (50.9%) reported quitting whereas 830 (49.1%) were still smoking at the 1-year follow-up. Stoppers were younger (57 vs. 58 years, p&amp;lt;0.001), more likely to be male (82.8% vs. 77.7%, p=0.008) and have presented with STEMI (77.0% vs. 71.0%, p=0.005), and less likely to have had a previous AMI (6.6% vs. 13.3%, p&amp;lt;0.001) than continuers. Smoking cessation was more common in patients with a more severe AMI characterised by a greater extent of myocardial injury (in-hospital median peak creatine kinase level 1291 IU/L vs. 1101 IU/L, p=0.012), at least one in-hospital complication (13.9% vs. 9.9%, p=0.01), and participation in a rehabilitation programme (83.7% vs. 68.8%, p&amp;lt;0.001). Stoppers more frequently implemented other favourable lifestyle changes, such as dietary changes (56.2% vs. 45.2%, p&amp;lt;0.001) and increased physical activity (54.6% vs. 37.7%, p&amp;lt;0.001) than continuers. Self-reported weight gain was more prevalent among those who quit smoking (44.0% vs. 19.7%, p&amp;lt;0.001). Conclusions In Switzerland, half of the patients with AMI who were active smokers at the time of AMI, reported to have stopped smoking 1 year after the index event. Smoking cessation was associated with participation in a rehabilitation programme and occurred more often in patients with larger AMI sizes, higher in-hospital complication rates and more frequent implementation of other favourable lifestyle changes after AMI. The significant weight gain after smoking cessation seems to represent a major issue that should specifically be addressed.

Low-density lipoprotein cholesterol goal attainment with "inclisiran first" versus usual care in patients with atherosclerotic cardiovascular disease

Abstract Background Rapid and sustained attainment of guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals is critical for patients with atherosclerotic cardiovascular disease (ASCVD). In VICTORION-INITIATE, inclisiran administered twice-yearly by a healthcare professional earlier in the treatment pathway allowed more patients with ASCVD to achieve and sustain LDL-C goals vs current usual care (UC). Purpose To evaluate cumulative LDL-C exposure in the overall population and LDL-C goal attainment and safety in subgroups of participants (type of ASCVD, timing of ASCVD event, and history of statin intolerance) who received an "inclisiran first" implementation strategy (IF; adding inclisiran immediately on failure to achieve LDL-C &amp;lt;70 mg/dL [1.8 mmol/L] with maximally tolerated statins) compared with UC. Methods VICTORION-INITIATE was a 330-day, prospective, pragmatically designed trial that randomised participants 1:1 (stratified by insurance status) to IF (open-label inclisiran 284 mg at Days 0, 90 and 270 plus UC) or UC alone (lipid management directed by treating physician’s discretion). The study took place at 45 sites across 20 states in the USA. Treating physicians had access to LDL-C measurements and were encouraged to intensify treatment per clinical practice guidelines. This prespecified subgroup analysis evaluated LDL-C goal attainment by timing of the most recent ASCVD event (&amp;lt;1 year/≥1 year prior to consent), ASCVD subtype (coronary heart disease [CHD], peripheral arterial disease [PAD], and cerebrovascular disease [CVD]) and statin intolerance status. Cumulative LDL-C exposure over time in the overall population and safety by subgroup were also evaluated. Results Of 450 patients randomised to IF or UC, 11.1% and 84.2% had an ASCVD event &amp;lt;1 year or ≥1 year prior to consent, respectively; 91.8%, 18.2% and 14.7% had a history of CHD, CVD or PAD, and 25.8% were statin intolerant. Cumulative exposure to LDL-C to Day 330 was lower in patients treated with IF vs UC (mean time-adjusted LDL-C: 42.4 mg/dL vs 90.7 mg/dL, Figure). Significantly more patients who received IF achieved LDL-C goals of &amp;lt;70 mg/dL and &amp;lt;55 mg/dL at Day 330 vs UC, irrespective of subgroup (Table). Across subgroups, the incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs were similar between IF and UC (IF: 52.6−71.2%, UC: 46.2−66.0% and IF: 10.7−28.3%, UC: 11.4−22.2%, respectively). Conclusions Participants with ASCVD and LDL-C &amp;gt;70 mg/dL who received IF had lower cumulative LDL-C exposure over the study period than those treated with UC. IF resulted in rapid and sustained achievement of LDL-C goals regardless of ASCVD subtype, event timing and statin intolerance. The safety profile of IF was consistent across the subgroups analysed.

Efficacy of combination lipid lowering therapy in achieving low density lipoprotein cholesterol targets after one month of event in patients with acute coronary syndrome

Abstract Introduction Rapid reduction in low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of recurrent events in patients with acute coronary syndrome (ACS) with benefits proportional to LDL-C reduction. Early use of combination lipid-lowering therapy (LLT) is therefore recommended. Proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) combined with high-intensity statins (HIS) improve LDL-C goal attainment but are unaffordable for many patients in India and worldwide. Purpose We share our experience with the use of dual RE (rosuvastatin plus ezetimibe) and triple REB (rosuvastatin plus ezetimibe and bempedoic acid) combination LLT in patients admitted with ACS. Methods All ACS patients admitted to our institute over one year (January 2023 to December 2023) were considered in this retrospective analysis. Those with unavailable lipid profile reports, either at the time of ACS or at 1-month follow-up, were excluded. Clinical and laboratory details were obtained from hospital records. The primary objective was to assess the percentage change in LDL-C levels from index event to 4 weeks follow-up. Results A total of 299 patients were included, out of which 60 were on HIS alone, 71 were on RE, and 168 were on REB (Figure). The majority (99%) of patients in the REB group were statin naïve, compared to the other two groups. The baseline mean LDL-C levels at the time of the index event were 95.3+30.5, 103.2+39.6, and 115.6+32.9 mg/dl, respectively (p&amp;lt;0.001) (Table). The mean LDL-C levels at four weeks post-ACS reduced to 52.9+21.2, 45.9+20.5, and 43.7+15.4 mg/dl, respectively (p&amp;lt;0.01). The percentage reduction in LDL-C level was 44.4%, 55.5%, and 62.2%, respectively (p&amp;lt;0.001). REB enabled 70.8% and 95.2% of patients to achieve the Lipid Association of India, and American College of Cardiology recommended LDL-C targets of &amp;lt;50 mg/dl and &amp;lt;70 mg/dl within 4 weeks. These target levels were achieved in 67.6% and 88.7% of patients on the dual RE therapy and 50% and 81.6% of patients, respectively, on HIS alone. Conclusion Our study demonstrates the capacity to rapidly achieve LDL-C goals after ACS with triple REB therapy, an affordable regimen compared to costly PCSK9i therapy.Figure.Lipid lowering strategies usedComparison of study groups

Multi-modal artificial intelligence-based prediction for cardiovascular mortality after transcatheter aortic valve implantation: a time-to-event survival prediction

Abstract Background Predicting long-term outcomes following Transcatheter Aortic Valve Implantation (TAVI) presents a significant challenge. Objective We aimed to predict post-TAVI long-term cardiovascular mortality using multimodal data and employing time-to-event artificial intelligence (AI) algorithms. Methods This study enrolled 3,973 consecutive patients from the prospective TAVI registry (between August 2007 and June 2023). Multimodal information was collected and extracted as numerical data for each patient, encompassing clinical history, medication, laboratory, procedural characteristics, ECG, angiography, echocardiography (TTE and TEE), and CT. Clinical outcomes were adjudicated by an independent clinical event committee. From the multimodal information, 147 features were extracted at baseline before the TAVI procedure. The datasets were divided into a training/validation set (80%) and a hold-out test set (20%) for model development and evaluation, respectively. Cox-LASSO feature selection was employed to identify the most relevant features, followed by the implementation of Random Survival Forest (RSF), Gradient Boosting Survival Analysis (GBSA), and Survival Support Vector Machine (SSVM) to predict the timing and occurrence of cardiac death events in patients. Feature selection, model parameters, and hyperparameters selection were performed using 10-fold cross-validation on the training set. Model performance was evaluated using different metrics, such as the concordance index (c-index) and cumulative Area Under the Curve (C-AUC) on a 20% untouched test set. Results In the patient cohort, 28.4% experienced cardiovascular death. Features were selected from various modalities, including 22 from clinical history, two from medication, eight from laboratory tests, one from ECG, eight from CT scans, and five from echocardiography and angiography. In the univariate Cox-PH model, all features exhibited a C-index ranging from 0.50 to 0.57. In the test set, the conventional Multivariate Cox-PH model achieves a c-index of 0.59 (C-AUC: 0.56). RSF, GBSA, and SSVM achieve a C-index of 0.70 (C-AUC: 0.69), 0.66 (C-AUC: 0.64), and 0.69 (C-AUC: 0.68), respectively, in the holdout test set. Conclusion Integrating multimodal information, encompassing imaging, signal, laboratory data, and clinical history, with AI algorithms has markedly enhanced the prediction of long-term cardiac outcomes following the TAVI procedure. The initially developed model can predict the probability of cardiac death up to 10 years. Furthermore, the RFS model significantly outperformed the conventional Cox model in predicting time-to-event outcomes.

Cardiac troponin elevation in intracerebral hemorrhage patients may rather reflect acute myocardial damage than acute myocardial infarction

Abstract Background Patients with acute ischemic stroke (AIS) and elevated cardiac troponin (cTn) have worse functional and mortality-related outcome. While elevated cTn is also frequently observed in patients with intracerebral hemorrhage (ICH), routine invasive coronary angiography should not be performed on these patients. Existing data on correlation of cTn elevation with patient outcome and the underlying causes in this specific patient group are sparse and largely heterogeneous. Purpose To investigate the clinical variables that predict cTn elevation in patients with ICH and the impact of cTn elevation on intrahospital mortality and functional outcome. Methods Our long-term Stroke Database was screened for ICH patients with high-sensitivity (hs) cTn measurement on admission (from 2015 onwards). Baseline characteristics, intrahospital mortality and functional outcome at discharge were compared between the groups with and without cTn elevation (hs-cTnI &amp;gt; vs. ≤0.045 µg/L). In addition, clinical variables with suspected significance for cTn elevation were analyzed for their predictive value. Results A total of 93/498 patients with ICH (18.7%; mean age 73±15 years, 53.8% females) were found to have a cTn elevation. Regarding etiology, 38.7% had an ICH occurring after AIS and 31.2% had a hypertensive ICH (each p=NS between groups). Patients with cTn elevation did not have a more pronounced cardiovascular risk profile and had a comparably low prevalence of coronary artery disease (CAD; 18.5%, p=NS). However, they were significantly less likely to be on oral anticoagulation at the time of the bleeding event (7.5 vs. 18.0%, p=0.013). CTn elevation had no negative impact on intrahospital mortality (21.5 vs. 20.5%, p=NS) or functional outcome at discharge (NIHSS score 10 (2; 26) vs. 9 (2; 22) points, mRS 5 (3; 5) vs. 5 (3; 5) points, each p=NS). Increasing NIHSS score on admission (p=0.021, OR 1.084 [1.012-1.160]), mRS ≥4 on admission (p=0.005, OR 2.207 [1.180-2.826]), infratentorial bleeding localization (p=0.034, OR 4.899 [1.132-21.207]) and aortic valve stenosis ≥ intermediate (p&amp;lt;0.001, OR 8.435 [2.429-29.294]) predicted cTn elevation. In contrast, severely impaired left ventricular function, CAD, atrial fibrillation, intraventricular hemorrhage or ICH occurring after AIS had no predictive value. Conclusions Almost one fifth of patients with ICH had an elevated cTn. Unlike in AIS, in ICH cTn elevation was not associated with a worse functional or mortality-related intrahospital outcome. In particular, severe functional impairment on admission, reflecting severe ICH, or infratentorial hemorrhage localization, thought to affect the autonomic nervous system, was predictive of concomitant myocardial cell damage. CAD was rare overall. This could indicate that the cTn elevation in connection with ICH is primarily related to acute myocardial damage along the brain-heart axis and less to myocardial infarction.