Onset Of Events Research Articles

Endoplasmic reticulum stress in acute lung injury and pulmonary fibrosis.

Pulmonary fibrosis (PF) is a progressive and irreversible lung disease that leads to diminished lung function, respiratory failure, and ultimately death and typically has a poor prognosis, with an average survival time of 2 to 5 years. Related articles suggested that endoplasmic reticulum (ER) stress played a critical role in the occurrence and progression of PF. The ER is responsible for maintaining protein homeostasis. However, factors such as aging, hypoxia, oxidative stress, or inflammation can disrupt this balance, promoting the accumulation of misfolded proteins in the ER and triggering ER stress. To cope with this situation, cells activate the unfolded protein response (UPR). Since acute lung injury (ALI) is one of the key onset events of PF, in this review, we will discuss the role of ER stress in ALI and PF by activating multiple signaling pathways and molecular mechanisms that affect the function and behavior of different cell types, with a focus on epithelial cells, fibroblasts, and macrophages. Linking ER stress to these cell types may broaden our understanding of the mechanisms underlying lung fibrosis and help us target these cells through these mechanisms. The relationship between ER stress and PF is still evolving, and future research will explore new strategies to regulate UPR pathways, providing novel therapeutic targets.

Cohort profile of a prospective cohort study among middle-aged community-dwellers in rural Vietnam: The Khánh Hòa cardiovascular study.

Disease burden associated with cardiovascular diseases (CVDs) in low- and middle-income countries has been on an increasing trend in the past decades. Despite the worldwide genetic, cultural, and environmental variations in determinants of CVDs, few studies have attempted the identification of risk factors of CVDs in low- and middle-income countries. This article aims to introduce the Khánh Hòa Cardiovascular Study, a prospective cohort study among middle-aged community dwellers in rural Khánh Hòa, Vietnam. A total of 3000 individuals, aged 40-60 years at baseline, participated in the baseline survey conducted from June 2019 to June 2020 and will be followed up for the subsequent 10 years. The baseline survey collected information on sociodemographic variables, disease history, lifestyle, social environment, and mental health via questionnaires, physical examinations, and biochemical measurements. Information on the incidence of severe health outcomes (i.e., mortality, CVDs, and cancer) has been and will be collected using a study-specific disease registry. Results showed that the prevalences of excess body weight (body mass index ≥25 kg/m2), hypertension, diabetes mellitus, and dyslipidemia were 25.9%, 39.6%, 10.2%, and 45.1%, respectively. Furthermore, by March 2023, 21 participants had died, including 5 CVD deaths and 12 cancer deaths. Moreover, we recorded 22 and 31 cases of nonfatal CVDs and cancer, respectively. These results suggest that many rural residents in Vietnam have high cardiometabolic risk, and underscore the importance of advancing research to identify risk factors and prevent the onset of serious health events.

Cross-Seasonal Effect on Tropical Pacific Precipitation: Implication of South Pacific Quadrupole Simulation in CMIP6

Abstract The tropical Pacific convergence zone plays a crucial role in the global climate system. Previous research studies emphasized the cross-seasonal influence of the South Pacific quadrupole (SPQ) mode on the tropical Pacific climate. This study assesses the relationship between austral summer SPQ and austral winter tropical precipitation in phase 6 of the Coupled Model Intercomparison Project (CMIP6) models. The analysis emphasizes the historical experiments conducted within this time frame, spanning from 1979 to 2014. Our findings reveal that the SPQ is accurately represented in all CMIP6 models, but the connection between SPQ and precipitation is inadequately simulated in most models. To investigate the reasons behind these intermodel differences in reproducing SPQ-related processes, we categorize models into two groups. The comparisons demonstrate that the fidelity of model simulations in replicating the SPQ–tropical precipitation relationship hinges significantly on their capacity to reproduce the positive wind–evaporation–sea surface temperature (WES; SST) feedback over both the southwestern Pacific (25°–10°S; 150°E–160°W) and the southeastern Pacific (30°–10°S; 140°–80°W). This positive WES feedback propagates the SPQ signal into the tropics, intensifying the meridional gradient of SST anomaly in the tropical western-central Pacific, which consequently amplifies convection and rainfall in that area. In the group of models that failed to simulate this relationship accurately, the weakened WES feedback can be traced back to biases in wind speed and its variation. Furthermore, this WES feedback establishes a connection between SPQ and El Niño–Southern Oscillation (ENSO). A better rendition of the SPQ–tropical rainfall connection tends to result in a better simulation of the onset of SPQ-related ENSO events. As a result, this study advances our comprehension of extratropical impacts on the tropics, with the potential to enhance the accuracy of tropical climate simulation and prediction. Significance Statement Tropical rainfall plays an important role in the global climate system. Beyond the well-known influence of El Niño–Southern Oscillation (ENSO) on the tropical rainfall, the sea surface temperature (SST) anomaly in the South Pacific has a cross-seasonal impact on the precipitation over the tropical Pacific via air–sea coupled processes. Such SST anomaly pattern shows a quadrupole structure in the extratropical South Pacific, known as the South Pacific quadrupole (SPQ) mode. However, the relationship between SPQ and tropical precipitation remains poorly simulated in most state-of-the-art climate models. One primary reason for this gap between observed and simulated relationships is the underestimation of wind speed and its variation over the south tropical Pacific in these models. This limitation undermines their ability to accurately represent the air–sea interactions that drive tropical precipitation patterns, leading to inaccuracies in simulations. Our study aims to bridge this knowledge gap by enhancing our understanding of the extratropical effects on the tropical Pacific. By exploring the mechanisms underlying the SPQ–precipitation connection, we expect to improve the simulation and prediction capabilities of tropical climate models, thereby enhancing our ability to forecast and adapt to future climatic changes.

Insights of Dynamic Forcing Effects of MJO on ENSO from a Shallow Water Model

Abstract The Madden–Julian oscillation (MJO) is believed to play a significant role in triggering El Niño–Southern Oscillation (ENSO) events and affect the dynamics of ENSO. In this study, the dynamic forcing effects of MJO on the equatorial oceanic dynamic fields and the onsets of different types of ENSO events are investigated through sensitive experiments using spatiotemporally filtered forcing based on an anomalous shallow water model. The comparisons between observations and model responses provide meaningful insights into the extent of MJO’s impacts on sea surface dynamics relative to other atmospheric variabilities. The following conclusions are made. First, the MJO-forced perturbations on zonal currents are stronger and more significant than those on sea surface heights. Second, MJO is essential for improving zonal current simulation in the western-central Pacific and generating activity centers of zonal currents in the eastern Pacific in the model. Third, MJO tends to contribute to the onset of El Niño events rather than La Niña events. Strong intraseasonal oceanic Kelvin waves forced by MJO are confirmed in simulations during the onset stages of the 1997/98 and 2004/05 events. The 120-day running standard deviations of zonal current and sea surface height anomaly series forced by MJO exhibit positive skewness similar to those of the 20–100-day band-passed observational series. Yet, not all the onsets of historical ENSO events are in company with strong MJO-related perturbations. Additionally, the wind stress formula can amplify the responses of zonal current and sea surface height anomalies to synoptic forcings with periods shorter than 20 days through entraining lower-frequency variabilities. Significance Statement The Madden–Julian oscillation (MJO) is believed to be able to trigger El Niño–Southern Oscillation (ENSO) events and influence our understanding of the fundamental nature of ENSO. In this study, spatiotemporally filtered forcing experiments are implemented on an anomalous shallow water model. The results show that MJO is more important for improving the simulation of surface zonal currents rather than the sea surface heights and tends to contribute to the onset of El Niño events rather than La Niña events through triggering strong intraseasonal oceanic Kelvin waves.

A Retrospective Study Reviewing Timing to Onset of Habitual Psychogenic Non-Epileptic Seizures in a Home Video Telemetry Cohort

Objectives: This study aimed to investigate the onset time to habitual psychogenic non-epileptic seizures (PNES) in adults referred to Guy’s and St Thomas’ Neurophysiology Department for home video telemetry (HVT) with a clinical question of PNES. The primary objective was to determine the optimal time window for HVT recording for patients with suspected PNES to try to improve the allocation of clinical resources. The secondary objective was to explore any potential association between time to habitual PN ES onset and demographic indexes and other clinical, neuro-radiological and semiological findings. Methods: We performed a retrospective analysis of our XLTEK database between 2019 and 2020. A multifactorial analysis of PNES semiologic subtypes, patient demographics, psychiatric comorbidities and neuroimaging was conducted to explore their impact on time to PNES within an HVT study. People who had at least one typical PNES during their recording were included. The exclusion criteria included people who had the test performed without video recording. The total number of participants was 37. The data were extracted from our local XLTEK database. Statistical analyses using Mann–Whitney U and Fischer exact tests were carried out. Results: The mean time to first habitual PNES onset was seven hours, with a mean recording duration of 46 h. The most commonly occurring event type was blank spells (12, 32%), with the least common presentation being déjà vu (1, 3%). There was a significant association between time to PNES onset and male sex (p = 0.04). There was a significant association between time to PNES onset and abnormal MRI findings (p = 0.02). Particular PNES semiologic subtypes were not significantly linked with PNES onset time. Conclusions: Our study highlights that on average, patients with PNES will rapidly have their first habitual event within an HVT study (mean time to event onset of seven hours), consistent with the current literature. This raises the question of whether HVT study duration could be reduced to release study resources and aid departmental efficiencies. We also observe the novel finding that men presented significantly earlier with their habitual PNES event than women, and that abnormal imaging findings were also significantly associated with an earlier time to event onset, although the reason for this association is yet to be determined.

Glucagon-like peptide-1 receptor agonists and impaired gastric emptying: a pharmacovigilance analysis of the US Food and Drug Administration adverse event reporting system

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) potentially increase the risk of pulmonary aspiration resulting from impaired gastric emptying (IGE). We evaluated the association between GLP-1RAs and IGE using the US Food and Drug Administration Adverse Event Reporting System (FAERS). MethodsWe analysed FAERS data from 2004 Q1 to 2024 Q1, identifying the top 10 drugs linked to IGE and determining the proportion of GLP-1RA use. Disproportionality analysis using the reporting odds ratio was conducted to assess the relative IGE risk for each drug. Logistic regression analysed the impact of age, weight, and sex on IGE risk. Cumulative incidence and time to onset of IGE events were examined using Kaplan–Meier and Weibull shape parameter tests. ResultsAmong the top 10 drugs associated with IGE reports, five were GLP-1RAs, accounting for 49.5% (982/1982) of cases. Dulaglutide (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.94–1.00, P=0.033) and semaglutide (OR 0.96, 95% CI 0.94–0.97, P=0.001) showed lower IGE risk with older age. For exenatide, higher weight (OR 0.99, 95% CI 0.98–1.00, P=0.033) and male sex (OR 0.39, 95% CI 0.20–0.68, P=0.033) were associated with lower IGE risk. Median onset times ranged from 40.5 days (semaglutide) to 107.5 days (tirzepatide) from intitiation of therapy. The Weibull shape parameter β was <1 for all GLP-1RAs, indicating a higher IGE risk early in treatment. ConclusionsGLP-1RAs were notably associated with reports of impaired gastric emptying in the FAERS. Age, weight, and sex were significantly associated with impaired gastric emptying risk for certain GLP-1RAs. IGE events tended to occur early in treatment, with risk diminishing over time. These findings provide valuable references for future research on perioperative safety with GLP-1RAs.

Reconstruction of long-term sublethal effects of warming on a temperate coral in a climate change hotspot.

The impact of warming on zooxanthellate corals is widespread, from tropical to temperate seas, with its associated mortalities causing global concern. The temperate coral Cladocora caespitosa is the only zooxanthellate coral with reef building capacity in the Mediterranean Sea, a climate change hotspot with warming rates triple the global average. During the past two decades, C. caespitosa populations have suffered severe mortality events associated with marine heatwaves (MHWs). However, with monitoring efforts beginning, at best, in the 2000s, the occurrence of MHWs before that period, as well as the sublethal effects of these events remain poorly understood. Here, we use sclerochronology to reconstruct the histories of past stress events and long-term sublethal effects on C. caespitosa in three locations along a latitudinal gradient within the NW Mediterranean Sea, each with different environmental conditions. Skeletal extension, density and calcification rates were compared with the insitu seawater temperature of each site to assess their relationship. Furthermore, we assessed the occurrence of skeletal growth anomalies to reconstruct stress events between 1991 and 2021, a period that encompasses the onset and evolution of warming-related mass mortality events in the NW Mediterranean Sea. Our results reveal a positive association between calcification and temperature, following a latitudinal temperature gradient. However, the evolution of the likelihood distribution of growth rates in the warmest site (Columbretes Islands) since the 1990s indicates a decrease in linear extension and calcification rates during the most recent years. With the increase in the frequency of MHWs and growth anomalies during the last decade, this decline suggests recurrent physiological stress events. These results unravel information on the long-term impacts of warming on coral growth and highlight the potential of applying sclerochronology to reconstruct the sublethal effects of warming using C. caespitosa.

Climatic oscillation based 3-dimensional drought risk assessment over India

Drought risk assessment is essential for the efficient design of water resource infrastructures and agricultural planning. Conventional drought studies define droughts either in a spatial or temporal framework without considering the simultaneous temporal and spatial progression of droughts. Spatiotemporal drought (SPD), a dynamic and complex phenomenon, has been relatively understudied due to the challenges in developing algorithms for their identification. In this study, we use a 3-dimensional drought identification framework to identify the SPD events across India. Further, as large-scale ocean-atmospheric phenomena namely El Niño Southern Oscillation (ENSO) and Equatorial Indian Ocean Oscillation (EQUINOO) play an important role in modulating the occurrence of droughts in India, we investigated the influence of these climatic oscillations on SPD characteristics across different climatic regions of India. Further, ENSO-based drought risk assessment using drought characteristics and the synergy between univariate and multivariate drought risks are also evaluated. Results show that 1) there are significant seasonal and spatial variations in occurrences and magnitude of SPD characteristics for the different climate phases. SPDs during the ENSO positive (El Niño) and the EQUINOO negative phases have higher severity, especially over the monsoon core region. In northwest India, the median drought severity during El Niño events is over three times higher than La Niña events. Across most of India, a major portion of SPD event onset occurs during the monsoon seasons, however in the north-western and south-eastern regions an equal portion of drought onset occurs during the pre-monsoon and post-monsoon season, respectively. 2) Further, the ENSO-based drought risk assessment reveals that severe and longer-duration SPD events are associated with El Niño phases, making ENSO a crucial factor in drought frequency analysis. 3) The synergy between the univariate and multivariate drought risks conditioned on ENSO reveal that overall drought risks are linked to the magnitude of individual drought characteristics which have a strong association with ENSO phases. Thus, design criteria for drought resilient infrastructure should be based on the dominant drought characteristics influenced by ENSO phases for effective drought risk assessment. Overall, the study underscores the significant impact of ENSO on SPDs in India and the importance of incorporating ENSO information in drought frequency analysis for reliable risk assessments.

Near-Inertial Oscillations Induced by Winter Monsoon Onset in the Southwest Taiwan Strait

The near-inertial motion in ocean surface currents directly reflects the energy transported by wind towards the surface layer, playing an important role in climate regulation and energy balance. Previous studies have mainly focused on near inertial oscillations (NIOs) induced by tropical cyclones in the Taiwan Strait, with few reports on near inertial oscillations induced by monsoon onset. Using high-frequency radar observations, we detected an amplification of NIOs induced by the winter monsoon onset. While not as strong as NIOs induced by tropical cyclones, the near-inertial current (NIC) induced by winter monsoon onset in the Taiwan Strait has peak speeds reaching up to 5.2 cm/s and explaining up to 0.7% of non-tidal variance. This study presents observational results of NIOs during three monsoon onset events, and analyzes the impact of winds and temperature changes on NIOs. Temporal and spectral analysis reveals that the monsoon onset is the primary driver behind the formation of NIOs. Results indicate that near-inertial kinetic energy is relatively lower in shallower waters, such as the Taiwan Bank, compared to deeper regions. Furthermore, by integrating the air and sea surface temperature from reanalysis products, we have examined the abrupt changes in sea surface temperature (SST) before and after monsoon onset and their correlation with NIOs. The findings suggest that temperature falling favors the intensification of NICs during monsoon onset, and a lack of significant SST changes precludes the triggering of notable NICs. These insights enhance our understanding of the mechanisms driving NIOs and their roles in seawater mixing.

A randomized trial of early cardiotoxicity in breast cancer patients receiving postoperative IMRT with or without serial cardiac dose constraints.

Optimal cardiac dose constraints in breast cancer (BC) patients undergoing postoperative intensity-modulated radiation therapy (IMRT) are unclear, although as low as possible is recommended. This trial proposes serial cardiac dose constraint to optimize cardiac safety. Postoperative BC patients eligible for anthracycline/taxanes-based chemotherapy or HER2-targeted therapy were randomized to cardiac safety arm with prespecified mean heart dose (MHD) (≤6 Gy), V30 (≤20%), and V10 (≤50%) constraints, or to a control arm with in-house protocol (mainly MHD ≤8 Gy). The primary endpoint was cumulative incidence of newly onset cardiac events within 1-year post-RT. An exploratory analysis examined the relationship between whole heart dose metrics and those of substructures. Of 199 participants, 93 were in the cardiac safety and 106 in the control arm. The cardiac safety group showed lower MHD, V10, and V30. The 1-year cardiac event incidence was slightly lower in the cardiac safety group (19.4%) compared to controls (24.9%). The LVEF and diastolic dysfunction rates were 0% and 5.4% in the study arm, and 1.9% and 8.8% in the control arm, respectively. The LAD, LV, and RV received the highest doses for left-sided patients. For right-sided patients, RA, RCA, and RV were most irradiated. The MHD, V10, and Dmax of heart significantly correlated with all substructure doses in either laterality. Our study supports the early cardiac safety profile using IMRT in BC patients receiving cardiac-toxic systemic therapy, with serial cardiac dose constraints. Combined constraints on MHD and dose-volume parameters are representative of the cardiac substructure dose.

Global Prediction of Flash Drought Using Machine Learning

AbstractFlash droughts are rapidly developing extreme weather events with sudden onset and quick intensification. Global prediction of flash droughts at sub‐seasonal time scales remains a great challenge. Current state‐of‐the‐art dynamic models subject to large errors and demonstrate low skills in global flash drought prediction. Here, we develop a machine learning‐based framework that uses meteorological forecasts as inputs to predict global root‐zone soil moisture and flash droughts from 1 day to 2 week lead times. The results indicate that 33% and 24% global flash drought onset and termination events can be correctly predicted by machine learning at 7 day lead time, versus 19% and 11% fractions by state‐of‐the‐art dynamic model. The developed machine learning model demonstrates substantial improvements over dynamic model in global soil moisture prediction, and thus enhances global flash drought forecasting skills in space and time. The presented framework may benefit global flash drought prediction and early warning at sub‐seasonal scales.

An Unobtrusive and Lightweight Ear-worn System for Continuous Epileptic Seizure Detection

Epilepsy is one of the most common neurological diseases globally (around 50M people globally). Fortunately, up to 70% of people with epilepsy could live seizure-free if properly diagnosed and treated, and a reliable technique to monitor the onset of seizures could improve the quality of life of patients who are constantly facing the fear of random seizure attacks. The current gold standard, video-EEG (v-EEG), involves attaching over 20 electrodes to the scalp, is costly, requires hospitalization, trained professionals, and is uncomfortable for patients. To address this gap, we developed EarSD , a lightweight and unobtrusive ear-worn system to detect seizure onsets by measuring physiological signals behind the ears. This system can be integrated into earphones, headphones, or hearing aids, providing a convenient solution for continuous monitoring. EarSD is an integrated custom-built sensing - computing - communication ear-worn platform to capture seizure signals, remove the noises caused by motion artifacts and environmental impacts, and stream the collected data wirelessly to the computer/mobile phone nearby. EarSD 's ML algorithm, running on a server, identifies seizure-associated signatures and detects onset events. We evaluated the proposed system in both in-lab and in-hospital experiments at the University of Texas Southwestern Medical Center with epileptic seizure patients, confirming its usability and practicality.

Predicting major adverse cardiac events using radiomics nomogram of pericoronary adipose tissue based on CCTA: A multi-center study.

The evolution of coronary atherosclerotic heart disease (CAD) is intricately linked to alterations in the pericoronary adipose tissue (PCAT). In recent epochs, characteristics of the PCAT have progressively ascended as focal points of research in CAD risk stratification and individualized clinical decision-making. Harnessing radiomic methodologies allows for the meticulous extraction of imaging features from these adipose deposits. Coupled with machine learning paradigms, we endeavor to establish predictive models for the onset of major adverse cardiovascular events (MACE). To appraise the predictive utility of radiomic features of PCAT derived from coronary computed tomography angiography (CCTA) in forecasting MACE. We retrospectively incorporated data from 314 suspected or confirmed CAD patients admitted to our institution from June 2019 to December 2022. An additional cohort of 242 patients from two external institutions was encompassed for external validation. The endpoint under consideration was the occurrence of MACE after a 1-year follow-up. MACE was delineated as cardiovascular mortality, newly diagnosed myocardial infarction, hospitalization (or re-hospitalization) for heart failure, and coronary target vessel revascularization occurring more than 30days post-CCTA examination. All enrolled patients underwent CCTA scanning. Radiomic features were meticulously extracted from the optimal diastolic phase axial slices of CCTA images. Feature reduction was achieved through a composite feature selection algorithm, laying the groundwork for the radiomic signature model. Both univariate and multivariate analyses were employed to assess clinical variables. A multifaceted logistic regression analysis facilitated the crafting of a clinical-radiological-radiomic combined model (or nomogram). Receiver operating characteristic (ROC) curves, calibration, and decision curve analyses (DCA) were delineated, with the area under the ROC curve (AUCs) computed to gauge the predictive prowess of the clinical model, radiomic model, and the synthesized ensemble. A total of 12 radiomic features closely associated with MACE were identified to establish the radiomic model. Multivariate logistic regression results demonstrated that smoking, age, hypertension, and dyslipidemia were significantly correlated with MACE. In the integrated nomogram, which amalgamated clinical, imaging, and radiomic parameters, the diagnostic performance was as follows: 0.970 AUC, 0.949 accuracy (ACC), 0.833 sensitivity (SEN), 0.981 specificity (SPE), 0.926 positive predictive value (PPV), and 0.955 negative predictive value (NPV). The calibration curve indicated a commendable concordance of the nomogram, and the decision curve analysis underscored its superior clinical utility. The integration of radiomic signatures from PCAT based on CCTA, clinical indices, and imaging parameters into a nomogram stands as a promising instrument for prognosticating MACE events.

The time between symptom onset and various clinical outcomes: a statistical analysis of MERS-CoV patients in Saudi Arabia.

In this study, we investigate the impact of demographic characteristics on Middle East respiratory syndrome coronavirus (MERS-CoV) cases in Saudi Arabia, specifically focusing on the time intervals between symptom onset and key events such as hospitalization, case confirmation, reporting and death. We estimate these intervals using data from 2196 cases occurring between June 2012 and January 2020, partitioning the data into four age groups (0-24 years, 25-49 years, 50-74 years and 75-100 years). The duration from symptom onset to hospitalization varies between age cohorts, ranging from 4.03 to 4.75 days, with the 75-100 age group experiencing the longest delay. The interval from symptom onset to case confirmation spans 5.83-8.24 days, and again, the 75-100 age group faces the lengthiest delay. The interval from symptom onset and case reporting ranges from 7.0 to 9.8 days, with the 75-100 age group experiencing the longest delay. The period from symptom onset to death varies across age groups (12.3-16.1 days), with elevated mortality rates during outbreaks. Importantly, we observe age-based differences in the risk of hospitalization and other measures of infection severity, including the probability of death conditional on hospitalization. Careful quantification of epidemiological characteristics, including inference of key epidemiological periods and assessments of differences between cases of different ages, plays a crucial role in understanding the progression of MERS-CoV outbreaks and formulating effective public health strategies to mitigate their impact.

Early Aptian development and OAE 1a-linked demise of a carbonate platform in the western Tethys: Lower Cretaceous of Sierra Mariola (South Iberian Paleomargin, SE Spain)

A carbonate platform succession of early Aptian age is described from the Sierra Mariola, which is located within the Prebetic Zone of the Betic External Zones (BEZ) of the Southern Iberian Palaeomargin, in SE Spain. The facies and stratigraphic architecture of the studied succession are described and analysed from multiple logged sections to characterize different depositional environments.The cyclic stacking of facies observed suggests a possible orbital forcing of climate transmitted to sedimentation. Superbundles are recognized describing two sequences of Regressive-Transgressive (R-T) evolution. Analysis of carbon-isotope data identifies both the interval before the hyperthermal event of the early Aptian Oceanic Anoxic Event (OAE 1a) and the onset of the latter event, with an abrupt change in sedimentation marking the demise of the carbonate platform. The field outcrop thus preserves a record of the transition from a greenhouse world to a hothouse event.

A mitochondrial redox switch licenses the onset of morphogenesis in animals.

Embryos undergo pre-gastrulation cleavage cycles to generate a critical cell mass before transitioning to morphogenesis. The molecular underpinnings of this transition have traditionally centered on zygotic chromatin remodeling and genome activation1,2, as their repression can prevent downstream processes of differentiation and organogenesis. Despite precedents that oxygen depletion can similarly suspend development in early embryos3-6, hinting at a pivotal role for oxygen metabolism in this transition, whether there is a bona fide chemical switch that licenses the onset of morphogenesis remains unknown. Here we discover that a mitochondrial oxidant acts as a metabolic switch to license the onset of animal morphogenesis. Concomitant with the instatement of mitochondrial membrane potential, we found a burst-like accumulation of mitochondrial superoxide (O2 -) during fly blastoderm formation. In vivo chemistry experiments revealed that an electron leak from site IIIQo at ETC Complex III is responsible for O2 - production. Importantly, depleting mitochondrial O2 - fully mimics anoxic conditions and, like anoxia, induces suspended animation prior to morphogenesis, but not after. Specifically, H2O2, and not ONOO-, NO, or HO•, can single-handedly account for this mtROS-based response. We demonstrate that depleting mitochondrial O2 - similarly prevents the onset of morphogenetic events in vertebrate embryos and ichthyosporea, close relatives of animals. We postulate that such redox-based metabolic licensing of morphogenesis is an ancient trait of holozoans that couples the availability of oxygen to development, conserved from early-diverging animal relatives to vertebrates.

Efficacy and safety of P2Y12 inhibitors plus aspirin versus aspirin alone in ischemic stroke or high-risk transient ischemic attack: a meta-analysis of randomized controlled trials

Abstract Background Patients with mild ischemic stroke or transient ischemic attack (TIA) have an increased risk of recurrent stroke within 90 days after the onset of the initial thrombotic event. Antiplatelet therapy plays an essential role in reducing the risk of stroke recurrence. However, data regarding the efficacy and safety of dual antiplatelet therapy (DAPT) with P2Y12 inhibitors (clopidogrel/ticagrelor) and aspirin versus aspirin monotherapy is limited. Purpose We performed an updated systematic review and meta-analysis to evaluate the effectiveness of DAPT versus aspirin monotherapy in patients with mild ischemic stroke or TIA in the light of new published evidence. Moreover, we investigated whether antiplatelet therapy started within 72 hours is effective in reducing recurrent stroke as compared to the conventionally used 24-hour time window for initiating DAPT. Methods PubMed/MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) that compared DAPT with aspirin plus clopidogrel to aspirin alone started within 24 hours or 72 hours in patients with acute mild ischemic stroke or high-risk TIA from inception to December 31st, 2023. A random-effects model was used to pool risk ratios (RRs) and 95% confidence intervals (CIs) for clinical endpoints. Results Five RCTs with 27,563 patients were included in this study. DAPT significantly reduced the risk of recurrent stroke by 23% (RR: 0.77; 95% CI: 0.70-0.83; p&amp;lt;0.00001), ischemic stroke by 26% (RR: 0.74; 95% CI: 0.68-0.81; p&amp;lt;0.00001), and major adverse cardiovascular events (MACE) by 23% (RR: 0.77; 95% CI: 0.71-0.84; p&amp;lt;0.00001). However, DAPT was associated with a significantly increased risk of moderate or severe bleeding (RR: 2.19; 95% CI: 1.38-3.48; p=0.0009) and hemorrhagic stroke (RR: 2.08; 95% CI: 1.13-3.82; p=0.02). No significant differences were observed for all-cause death (RR: 1.28; 95% CI: 0.95-1.71; p=0.10), cardiovascular death (RR: 1.38; 95% CI: 0.81-2.33; p=0.23), and myocardial infarction (RR: 1.63; 95% CI: 0.77-3.46; p=0.20). We performed sensitivity analysis based on the hazard ratio reported by RCTs which showed comparable results. Subgroup analysis based on treatment onset time (therapy initiation within 24 hours of thrombotic event vs therapy initiation within 72 hours of thrombotic event) showed that both strategies were effective in reducing the risk of recurrent stroke. Subgroup analysis based on the duration of DAPT (21 days vs. 90 days) showed that DAPT for 90 days was associated with an increased risk of moderate or severe bleeding as compared to therapy lasting for 21 days. Conclusion DAPT with P2Y12 inhibitors and aspirin reduces the risk of recurrent stroke and MACE but is associated with an increased risk of moderate or severe bleeding.

Loneliness in the elderly and disease development in European welfare regions: a longitudinal study

Abstract Healthy ageing research has brought a recent focus on the association between loneliness and disease. Regional differences on loneliness prevalence in the elderly across welfare systems, and its association with varying mortality rates, have recently been demonstrated. We hypothesise loneliness affects disease development in the elderly, impacted by socio-economic policies that characterise welfare systems in the EU. We use logistic regression models to assess the association between loneliness (R-UCLA scale) and onset of new chronic disease and disease events, in a European sample of people aged &amp;gt;50 (n = 40840), using the SHARE database, during 2013 - 22 (waves 5 to 9). Preliminary results from two subsequent waves (2015-17, n = 11870) show a statistically significant effect of persistent loneliness on disease onset (increase in new disease events), when adjusting for sex, age, previous illness, and other socio-economic covariates (AOR 1.22, 95%CI 1.08-1.39, p &amp;lt; 0.01). Notably, comparing to the Scandinavian welfare group, only Eastern European countries show higher odds of disease development (AOR 1.52, 95%CI 1.32-1.77, p &amp;lt; 0.001), while also having the highest incidence of new disease in our sample. Age and welfare group show the strongest association with the outcome of interest, followed by change in occupation (no longer employed). Our current analyses span a larger period (2013-22), and we are exploring additional mediators of this effect, such as behavioural and social activity-related variables. Additional analyses to control for unrelated disease (low biological plausibility) and a social isolation index, described in the literature, are added. Furthermore, we analyse the longitudinal association between loneliness and healthcare use, such as polypharmacy and consults. With this study, we aim to contribute decision-making in health in all policies, by increasing integration between health and social sectors, while considering different regional and welfare policies. Key messages • Understanding socio-economic and welfare mechanisms which impact health in the elderly allows for better cross-sector policy design, promoting healthier ageing. • Persistent feelings of loneliness affect disease development in the elderly, which appear to be worsened in some EU welfare groups, independently of socio-economic status.

Evaluating corticosteroid treatment strategies for cardiac sarcoidosis: analysis of the nationwide claims-based JROAD-DPC dataset

Abstract Background Corticosteroid-based immunosuppressive therapy is the cornerstone of treatment for cardiac sarcoidosis (CS), aimed at preventing severe adverse events including death, heart failure and lethal arrhythmic events. Nevertheless, data on the optimal initial dosing, appropriate tapering schedules, suitable maintenance dosages, and the recurrence rates among patients are insufficient. Purpose This study sought to scrutinize real-world data on corticosteroid therapy regimen for CS and to reassess optimal treatment protocols. Methods From the Japanese Diagnosis Procedure Combination database, 6,282 patients with hospitalized CS were identified between 2012 and 2022. Among them, 3,067 CS patients who were initiated on corticosteroid therapy during hospitalization were analyzed. We examined the baseline patient characteristics and treatment strategies for corticosteroid therapy, including starting dose, tapering period, maintenance dose, and their correlation with the onset of adverse events. Results The cohort had a mean age was 63±11 years, and 1,256 patients (41.0 %) were female. The starting dose of corticosteroids was 30.3±6.9 mg, with 88.6% of patients receiving a dose of ≧30 mg/day. The doses of corticosteroids at 30, 60, 90, 120, 150 and 180 days post-discharge were 21.4±9.8, 15.7±6.9, 12.2±5.7, 10.4±5.0, 9.3±4.5 and 9.0±4.6 mg, respectively. By day 180, 83.7% of the patients were maintained on ≦10 mg/day. However, 17.1 % of patients required an increase in corticosteroid dosage during the tapering course, primarily due to exacerbation of sarcoidosis. When analyzing only the group without corticosteroid escalation up to 180 days post-discharge, the average corticosteroid dose was 8.7±3.8 mg, with 95.3% of patients on ≦10 mg/day. We observed 965 re-hospitalization (31.5 %) during follow-up, with 58.8% of these patients having corticosteroid escalation to ≧30 mg, and 12.8% of patients received second-line immunosuppressive therapy, such as methotrexate. Conclusion The majority of CS patients were initiated on a corticosteroid regimen of 30 mg/day, which was subsequently tapered to below 10 mg/day by day 180. However, non-negligible number of patients experienced clinical events or relapse, underscoring the necessity for vigilant follow-up during corticosteroid therapy.Figure

Ankle brachial index,a non invasive tool predicts cardiovascular events after acute myocardial infarction:a 3 year follow -up study

Abstract Background / Introduction The ankle-brachial index (ABI) is a non-invasive tool that was initially used for the diagnosis of lower-extremity peripheral artery disease (PAD). It has been proven that ABI is a marker of atherosclerosis in other vascular sites and can therefore be used to predict cardiovascular events regardless the presence or not of PAD symptoms. Purpose This study aims to examine the prognostic value of ABI in the setting of acute myocardial infarction (MI), as up till now there is not enough relevant evidence. Method We followed up 441 patients [79% male;mean age 62 years;67% hypertnesive; 30% with diabetes mellitus (DM); 52% current smokers] who were hospitalized because of MI for a period of three years. All patients underwent baseline estimation of clinical and laboratory parameters during theri hospitalization.The ABI was measured according to established methodology using a certified automated device and abnormal ABI defined as a value ≤ 0.9. The primary endpoint was a composite of all-cause and cardiovascular death, as well as major cardiovascular events including decompensated heart failure, new acute coronary syndrome, cerebrovascular event, malignant arrhythmia, PAD event and new onset renal dysfunction. All events were assessed both in-hospital and within 3 years of follow-up. Results Our study population had a mean ABI of 1.1 (IQR: 1.00 to 1.18). With the use of reduced multivariate regression models ABI was proven to be a prognostic indicator for the in-hospital composite endpoint. Patients with an abnormal ABI had a threefold risk of in-hospital events [HR 2.93, 95% CI: 1.48-5.81, p=0.002]. After conducting multivariate analysis ABI maintained its predictive power of all-cause mortality [HR 2.88, 95% CI: 1.53 – 5.42, p=0.001], regardless of hypertension DM, LDL levels and smoking status of the study population in 3 years follow-up. Conclusion An impaired ABI is associated with greater risk of in-hospital events in patients with acute MI. Moreover, ABI emerges as an independent predictor of long-term all-cause mortality in those patients.The findings of this study suggest that subclinical and clinical PAD are associated with poor outcomes among patients with acute MI; thus, routine ABI tests enhance risk stratification and might carry important prognostic significance in these patients regardless of PAD symptoms.