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Abstract Background Pre-existing comorbidities increase the likelihood of post-stroke dysphagia. This study investigates comorbidity prevalence in patients with dysphagia after ischemic stroke. Methods The data of patients with acute ischemic stroke from two large representative cohorts (STROKE-CARD trial 2014–2019 and STROKE-CARD registry 2020–2022 – both study center Innsbruck, Austria) were analyzed for the presence of dysphagia at hospital admission (clinical swallowing examination). Comorbidities were assessed using the Charlson Comorbidity Index (CCI). Results Of 2054 patients with ischemic stroke, 17.2% showed dysphagia at hospital admission. Patients with dysphagia were older (77.8 ± 11.9 vs. 73.6 ± 14.3 years, p

BACKGROUND: Dyslipidemia is an independent risk factor for coronary heart disease (CHD). Standard lipid panel cannot capture the complexity of the blood lipidome (ie, all molecular lipids in the blood). To date, very few large-scale epidemiological studies have assessed the full spectrum of the blood lipidome on risk of CHD, especially in a longitudinal setting. METHODS AND RESULTS: Using an untargeted liquid chromatography-mass spectrometry, we repeatedly measured 1542 lipid species from 1835 unique American Indian participants who attended 2 clinical visits (≈5.5 years apart) and followed up to 17.8 years in the Strong Heart Family Study (SHFS). We first identified baseline lipid species associated with risk of CHD, followed by replication in a European population. The model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, low-density lipoprotein cholesterol, estimated glomerular filtration rate, education, and physical activity at baseline. We then examined the longitudinal association between changes in lipid species and changes in cardiovascular risk factors during follow-up. Multiple testing was controlled by the false discovery rate. We found that baseline levels of multiple lipid species (eg, phosphatidylcholines, phosphatidylethanolamines, and ceramides) were associated with the risk of CHD and improved the prediction accuracy over conventional risk factors in American Indian people. Some identified lipids in American Indian people were replicated in European people. Longitudinal changes in multiple lipid species (eg, acylcarnitines, phosphatidylcholines, and triacylglycerols) were associated with changes in cardiovascular risk factors. CONCLUSIONS: Baseline plasma lipids and their longitudinal changes over time are associated with risk of CHD. These findings provide novel insights into the role of dyslipidemia in CHD.

It has been previously proposed that glacial inception represents a bifurcation transition between interglacial and glacial states and is governed by the nonlinear dynamics of the climate–cryosphere system. To trigger glacial inception, the orbital forcing (defined as the maximum of summer insolation at 65° N and determined by Earth’s orbital parameters) must be lower than a critical level, which depends on the atmospheric CO2 concentration. While paleoclimatic data do not provide a strong constraint on the dependence between CO2 and critical insolation, its accurate estimation is of fundamental importance for predicting future glaciations and the effect that anthropogenic CO2 emissions might have on them. In this study, we use the novel Earth system model of intermediate complexity CLIMBER-X with interactive ice sheets to produce a new estimation of the critical insolation–CO2 relationship for triggering glacial inception. We perform a series of experiments in which different combinations of orbital forcing and atmospheric CO2 concentration are maintained constant in time. We analyze for which combinations of orbital forcing and CO2 glacial inception occurs and trace the critical relationship between them, separating conditions under which glacial inception is possible from those where glacial inception is not materialized. We also provide a theoretical foundation for the proposed critical insolation–CO2 relation. We find that the use of the maximum summer insolation at 65° N as a single metric for orbital forcing is adequate for tracing the glacial inception bifurcation. Moreover, we find that the temporal and spatial patterns of ice sheet growth during glacial inception are not always the same but depend on the critical insolation and CO2 level. The experiments evidence the fact that during glacial inception, ice sheets grow mostly in North America, and only under low CO2 conditions are ice sheets also formed over Scandinavia. The latter is associated with a weak Atlantic Meridional Overturning Circulation (AMOC) for low CO2. We find that the strength of AMOC also affects the rate of ice sheet growth during glacial inception.

Immunoglobulin M (IgM) autoantibodies to oxidation-specific epitopes (OSEs) can be present at birth and protect against atherosclerosis in experimental models. This study sought to determine whether high titers of IgM titers to OSE (IgM OSE) are associated with a lower risk of acute myocardial infarction (AMI) in humans. IgM to malondialdehyde (MDA)-LDL, phosphocholine-modified BSA, IgM apolipoprotein B100-immune complexes, and a peptide mimotope of MDA were measured within 24 h of first AMI in 4,559 patients and 4,617 age- and sex-matched controls in the Pakistan Risk of Myocardial Infarction Study. Multivariate-adjusted logistic regression was used to estimate odds ratio (OR) and 95% confidence interval for AMI. All four IgM OSEs were lower in AMI versus controls (P < 0.001 for all). Males, smokers and individuals with hypertension and diabetes had lower levels of all four IgM OSE than unaffected individuals (P < 0.001 for all). Compared to the lowest quintile, the highest quintiles of IgM MDA-LDL, phosphocholine-modified BSA, IgM apolipoprotein B100-immune complexes, and MDA mimotope P1 had a lower OR of AMI: OR (95% confidence interval) of 0.67 (0.58-0.77), 0.64 (0.56-0.73), 0.70 (0.61-0.80) and 0.72 (0.62-0.82) (P < 0.001 for all), respectively. Upon the addition of IgM OSE to conventional risk factors, the C-statistic improved by 0.0062 (0.0028-0.0095) and net reclassification by 15.5% (11.4-19.6). These findings demonstrate that IgM OSE provides clinically meaningful information and supports the hypothesis that higher levels of IgM OSE may be protective against AMI.

Summary: In 2021, an ultra-rapid rollout vaccination campaign in the Schwaz district, Tyrol, Austria, delivered the COVID-19 vaccine BNT162b2 to 66.9% of eligible residents (dose 1: March 11–16, dose 2: April 8–13). Alongside the campaign, we recruited 11,955 residents into the prospective study REDUCE, of whom 3,859 participated in a booster vaccination initiative (November 20–28, 2021). Over a 24-month follow-up, 1,672 participants had incident RT-PCR-confirmed SARS-CoV-2. Compared to other Tyrolean districts, effectiveness in reducing SARS-CoV-2 infection at months 1–9 versus months 10–24 was 81.6% (95% CI 80.0–83.2%; hazard ratio 0.18 [0.17–0.20]) versus 38.2% (35.8–40.6%; 0.62 [0.59–0.64]) among REDUCE participants, and 22.5% (20.5–24.4%; 0.78 [0.76–0.80]) versus 17.0% (16.2–17.8%; 0.83 [0.82–0.84]) in the entire Schwaz district, with substantial variability during follow-up. By March 2023, 61% of Schwaz residents had received booster vaccination versus 55% in other Tyrolean districts. Consequently, vaccinating individuals at high pace effectively reduced SARS-CoV-2 infections and achieved higher vaccination coverage.

We present transient simulations of the last glacial inception using the Earth system model CLIMBER-X with dynamic vegetation, interactive ice sheets, and visco-elastic solid Earth responses. The simulations are initialized at the middle of the Eemian interglacial (125 kiloyears before present, ka) and run until 100 ka, driven by prescribed changes in Earth's orbital parameters and greenhouse gas concentrations from ice core data. CLIMBER-X simulates a rapid increase in Northern Hemisphere ice sheet area through MIS5d, with ice sheets expanding over northern North America and Scandinavia, in broad agreement with proxy reconstructions. While most of the increase in ice sheet area occurs over a relatively short period between 119 and 117 ka, the larger part of the increase in ice volume occurs afterwards with an almost constant ice sheet extent. We show that the vegetation feedback plays a fundamental role in controlling the ice sheet expansion during the last glacial inception. In particular, with prescribed present-day vegetation the model simulates a global sea level drop of only ∼ 20 m, compared with the ∼ 35 m decrease in sea level with dynamic vegetation response. The ice sheet and carbon cycle feedbacks play only a minor role during the ice sheet expansion phase prior to ∼ 115 ka but are important in limiting the deglaciation during the following phase characterized by increasing summer insolation. The model results are sensitive to climate model biases and to the parameterization of snow albedo, while they show only a weak dependence on changes in the ice sheet model resolution and the acceleration factor used to speed up the climate component. Overall, our simulations confirm and refine previous results showing that climate–vegetation–cryosphere feedbacks play a fundamental role in the transition from interglacial to glacial states characterizing Quaternary glacial cycles.

Abstract The last deglaciation experienced the retreat of massive ice sheets and a transition from the cold Last Glacial Maximum to the warmer Holocene. Key simulation challenges for this period include the timing and extent of ice sheet decay and meltwater input into the oceans. Here, major uncertainties and forcing factors for the last deglaciation are evaluated. Two sets of transient simulations are performed based on the novel ice‐sheet reconstruction PaleoMist and the more established GLAC1D. The simulations reveal that the proximity of the Atlantic meridional overturning circulation (AMOC) to a bifurcation point, where it can switch between on‐ and off‐modes, is primarily determined by the interplay of greenhouse gas concentrations, orbital forcing and freshwater forcing. The PaleoMist simulation qualitatively replicates the Bølling‐Allerød (BA)/Younger Dryas (YD) sequence: a warming in Greenland and Antarctica during the BA, followed by a cooling northern North Atlantic and an Antarctic warming during the YD.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR 105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Climate tipping elements are large-scale subsystems of the Earth that may transgress critical thresholds (tipping points) under ongoing global warming, with substantial impacts on the biosphere and human societies. Frequently studied examples of such tipping elements include the Greenland Ice Sheet, the Atlantic Meridional Overturning Circulation (AMOC), permafrost, monsoon systems, and the Amazon rainforest. While recent scientific efforts have improved our knowledge about individual tipping elements, the interactions between them are less well understood. Also, the potential of individual tipping events to induce additional tipping elsewhere or stabilize other tipping elements is largely unknown. Here, we map out the current state of the literature on the interactions between climate tipping elements and review the influences between them. To do so, we gathered evidence from model simulations, observations, and conceptual understanding, as well as examples of paleoclimate reconstructions where multi-component or spatially propagating transitions were potentially at play. While uncertainties are large, we find indications that many of the interactions between tipping elements are destabilizing. Therefore, we conclude that tipping elements should not only be studied in isolation, but also more emphasis has to be put on potential interactions. This means that tipping cascades cannot be ruled out on centennial to millennial timescales at global warming levels between 1.5 and 2.0 ∘C or on shorter timescales if global warming surpassed 2.0 ∘C. At these higher levels of global warming, tipping cascades may then include fast tipping elements such as the AMOC or the Amazon rainforest. To address crucial knowledge gaps in tipping element interactions, we propose four strategies combining observation-based approaches, Earth system modeling expertise, computational advances, and expert knowledge.

The glacial–interglacial cycles of the Quaternary exhibit 41 kyr periodicity before the Mid-Pleistocene Transition (MPT) around 1.2–0.8 Myr ago and ∼ 100 kyr periodicity after that. From the viewpoint of dynamical systems, proposed mechanisms generating these periodicities are broadly divided into two types: (i) nonlinear forced responses of a mono- or multi-stable climate system to the astronomical forcing or (ii) synchronization of internal self-sustained oscillations to the astronomical forcing. In this study, we investigate the dynamics of glacial cycles simulated by the Earth system model of intermediate complexity CLIMBER-2 with a fully interactive carbon cycle, which reproduces the MPT under gradual changes in volcanic-CO2 degassing and regolith cover. We report that, in this model, the dominant frequency of glacial cycles is set in line with the principle of synchronization. It is found that the model exhibits self-sustained oscillations in the absence of astronomical forcing. Before the MPT, glacial cycles synchronize to the 41 kyr obliquity cycles because the self-sustained oscillations have periodicity relatively close to 41 kyr. After the MPT the timescale of internal oscillations becomes too long to follow every 41 kyr obliquity cycle, and the oscillations synchronize to the 100 kyr eccentricity cycles that modulate the amplitude of climatic precession. The latter synchronization occurs with the help of the 41 kyr obliquity forcing, which enables some terminations and glaciations to occur robustly at their right timing. We term this phenomenon vibration-enhanced synchronization because of its similarity to the noise-enhanced synchronization known in nonlinear science. While we interpret the dominant periodicities of glacial cycles as the result of synchronization of internal self-sustained oscillations to the astronomical forcing, the Quaternary glacial cycles show facets of both synchronization and forced response.

Background/Objectives: Antibodies against the hepatitis B surface antigen (anti-HBs) are a marker of immunity against hepatitis B virus (HBV) infections. There is uncertainty about the anti-HBs seroprevalence in the general population of Austria. Methods: We conducted a cross-sectional analysis in blood donors from the Federal State of Tyrol in Austria (August–September 2023) to estimate anti-HBs seroprevalence and median antibody levels. Results: We enrolled 3935 blood donors (median age 47.6 years [25th–75th percentile: 33.3–56.6]; 40.7% female), who were hepatitis B surface antigen negative and had no detectable HBV-DNA. Overall seroprevalence was 51.4% (95% CI: 49.8–52.9%). Anti-HBs seropositivity decreased with higher age (p < 0.001), with 70.3% (66.1–74.3%) being seropositive among participants < 25 years of age and 30.2% (24.2–36.9%) in those aged ≥ 65 years. More females than males were seropositive (54.3% [51.8–56.7%] vs. 49.4% [47.4–51.4%]; p = 0.003). Seroprevalence was significantly higher in urban than in rural areas in participants aged 40 to p = 0.045) and ≥55 years (p = 0.001). Among 2022 seropositive participants, the overall median anti-HBs antibody level was 539.3 IU/L (25th–75th percentile: 116.3–5417.0). Furthermore, 5% of the participants had an anti-HBs antibody level between 10 and Conclusions: Anti-HBs seroprevalence in blood donors from Tyrol, Austria, was 51.4% between August and September 2023 and differed across age, sex, and residence area. Catch-up vaccination programs, especially targeting the elderly living in rural areas, are needed to close HBV immunity gaps.

Driven primarily by variations in the earth's axis wobble, tilt, and orbit eccentricity, our planet experienced massive glacial/interglacial reorganizations of climate and atmospheric CO2 concentrations during the Pleistocene (2.58 million years ago (Ma)–11.7 thousand years ago (ka)). Even after decades of research, the underlying climate response mechanisms to these astronomical forcings have not been fully understood. To further quantify the sensitivity of the earth system to orbital-scale forcings, we conducted an unprecedented quasi-continuous coupled general climate model simulation with the Community Earth System Model version 1.2 (CESM1.2, ∼3.75∘ horizontal resolution), which covers the climatic history of the past 3 million years (3 Myr). In addition to the astronomical insolation changes, CESM1.2 is forced by estimates of CO2 and ice-sheet topography which were obtained from a simulation previously conducted with the CLIMBER-2 earth system model of intermediate complexity. Our 3 Ma simulation consists of 42 transient interglacial/glacial simulation chunks, which were partly run in parallel to save computing time. The chunks were subsequently merged, accounting for spin-up and overlap effects to yield a quasi-continuous trajectory. The computer model data were compared against a plethora of paleo-proxy data and large-scale climate reconstructions. For the period from the Mid-Pleistocene Transition (MPT, ∼1 Ma) to the late Pleistocene we find good agreement between simulated and reconstructed temperatures in terms of phase and amplitude (−5.7 ∘C temperature difference between Last Glacial Maximum and Holocene). For the earlier part (3–1 Ma), differences in orbital-scale variability occur between model simulation and the reconstructions, indicating potential biases in the applied CO2 forcing. Our model-proxy data comparison also extends to the westerlies, which show unexpectedly large variance on precessional timescales, and hydroclimate variables in major monsoon regions. Eccentricity-modulated precessional variability is also responsible for the simulated changes in the amplitude and flavors of the El Niño–Southern Oscillation. We further identify two major modes of planetary energy transport, which played a crucial role in Pleistocene climate variability: the first obliquity and CO2-driven mode is linked to changes in the Equator-to-pole temperature gradient; the second mode regulates the interhemispheric heat imbalance in unison with the eccentricity-modulated precession cycle. During the MPT, a pronounced qualitative shift occurs in the second mode of planetary energy transport: the post-MPT eccentricity-paced variability synchronizes with the CO2 forced signal. This synchronized feature is coherent with changes in global atmospheric and ocean circulations, which might contribute to an intensification of glacial cycle feedbacks and amplitudes. Comparison of this paleo-simulation with greenhouse warming simulations reveals that for an RCP8.5 greenhouse gas emission scenario, the projected global mean surface temperature changes over the next 7 decades would be comparable to the late Pleistocene glacial-interglacial range; but the anthropogenic warming rate will exceed any previous ones by a factor of ∼100.

RationaleProprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored.ObjectiveThis study sought to interrogate the novel relationship between PCSK9 and HDL in humans.Methods and resultsComparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation.ConclusionsThis study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL.

The carbon cycle component of the newly developed Earth system model of intermediate complexity CLIMBER-X is presented. The model represents the cycling of carbon through the atmosphere, vegetation, soils, seawater and marine sediments. Exchanges of carbon with geological reservoirs occur through sediment burial, rock weathering and volcanic degassing. The state-of-the-art HAMOCC6 model is employed to simulate ocean biogeochemistry and marine sediment processes. The land model PALADYN simulates the processes related to vegetation and soil carbon dynamics, including permafrost and peatlands. The dust cycle in the model allows for an interactive determination of the input of the micro-nutrient iron into the ocean. A rock weathering scheme is implemented in the model, with the weathering rate depending on lithology, runoff and soil temperature. CLIMBER-X includes a simple representation of the methane cycle, with explicitly modelled natural emissions from land and the assumption of a constant residence time of CH4 in the atmosphere. Carbon isotopes 13C and 14C are tracked through all model compartments and provide a useful diagnostic for model–data comparison. A comprehensive evaluation of the model performance for the present day and the historical period shows that CLIMBER-X is capable of realistically reproducing the historical evolution of atmospheric CO2 and CH4 but also the spatial distribution of carbon on land and the 3D structure of biogeochemical ocean tracers. The analysis of model performance is complemented by an assessment of carbon cycle feedbacks and model sensitivities compared to state-of-the-art Coupled Model Intercomparison Project Phase 6 (CMIP6) models. Enabling an interactive carbon cycle in CLIMBER-X results in a relatively minor slow-down of model computational performance by ∼ 20 % compared to a throughput of ∼ 10 000 simulation years per day on a single node with 16 CPUs on a high-performance computer in a climate-only model set-up. CLIMBER-X is therefore well suited to investigating the feedbacks between climate and the carbon cycle on temporal scales ranging from decades to >100 000 years.

Background Dyslipidemia is an independent risk factor for coronary heart disease (CHD). Standard lipid panel cannot capture the complexity of the blood lipidome (ie, all molecular lipids in the blood). To date, very few large‐scale epidemiological studies have assessed the full spectrum of the blood lipidome on risk of CHD, especially in a longitudinal setting. Methods and Results Using an untargeted liquid chromatography–mass spectrometry, we repeatedly measured 1542 lipid species from 1835 unique American Indian participants who attended 2 clinical visits (≈5.5 years apart) and followed up to 17.8 years in the Strong Heart Family Study (SHFS). We first identified baseline lipid species associated with risk of CHD, followed by replication in a European population. The model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, low‐density lipoprotein cholesterol, estimated glomerular filtration rate, education, and physical activity at baseline. We then examined the longitudinal association between changes in lipid species and changes in cardiovascular risk factors during follow‐up. Multiple testing was controlled by the false discovery rate. We found that baseline levels of multiple lipid species (eg, phosphatidylcholines, phosphatidylethanolamines, and ceramides) were associated with the risk of CHD and improved the prediction accuracy over conventional risk factors in American Indian people. Some identified lipids in American Indian people were replicated in European people. Longitudinal changes in multiple lipid species (eg, acylcarnitines, phosphatidylcholines, and triacylglycerols) were associated with changes in cardiovascular risk factors. Conclusions Baseline plasma lipids and their longitudinal changes over time are associated with risk of CHD. These findings provide novel insights into the role of dyslipidemia in CHD.

Using the climate model CLIMBER-X, we present an efficient method for assimilating the temporal evolution of surface temperatures for the last deglaciation covering the period 22000 to 6500 years before the present. The data assimilation methodology combines the data and the underlying dynamical principles governing the climate system to provide a state estimate of the system, which is better than that which could be obtained using just the data or the model alone. In applying an ensemble Kalman filter approach, we make use of the advances in the parallel data assimilation framework (PDAF), which provides parallel data assimilation functionality with a relatively small increase in computation time. We find that the data assimilation solution depends strongly on the background evolution of the decaying ice sheets rather than the assimilated temperatures. Two different ice sheet reconstructions result in a different deglacial meltwater history, affecting the large-scale ocean circulation and, consequently, the surface temperature. We find that the influence of data assimilation is more pronounced on regional scales than on the global mean. In particular, data assimilation has a stronger effect during millennial warming and cooling phases, such as the Bølling-Allerød and Younger Dryas, especially at high latitudes with heterogeneous temperature patterns. Our approach is a step toward a comprehensive paleo-reanalysis on multi-millennial time scales, including incorporating available paleoclimate data and accounting for their uncertainties in representing regional climates.

Summary: Background: Socioeconomic inequalities in cardiovascular disease risk begin early in life and are more pronounced in females than males later in life. Causal atherogenic traits explaining this are not well understood. We explored sex-specific associations between childhood socioeconomic position (SEP) and molecular measures of systemic metabolism across early life. Methods: Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort in southwest England. Pregnant women with an expected delivery date between 1991 and 1992 were invited to participate. Maternal education was the primary indicator of SEP. Concentrations of 148 metabolic traits from targeted metabolomics (nuclear magnetic resonance spectroscopy) from research clinics at ages 7, 15, 18 and 25 years were analysed. The sex-specific slope index of inequality (SII) in trajectories of metabolic traits was estimated using multilevel models. Findings: Total number of participants included was 6537 (12,543 repeated measures). Lower maternal education was associated with more adverse levels of several atherogenic lipids and key metabolic traits among females at age 7 years, but not males. For instance, SII for very small very-low-density lipoprotein (VLDL) concentrations was 0.16SD (95% CI: 0.01, 0.30) among females and −0.02SD (95% CI: −0.16, 0.13) among males. Between 7 and 25 years, inequalities widened among females and emerged among males particularly for VLDL particle concentrations, apolipoprotein-B concentrations, and inflammatory glycoprotein acetyls. For instance, at 25 years, SII for very small VLDL concentrations was 0.36SD (95% CI: 0.20, 0.52) and 0.22SD (95% CI: 0.04, 0.40) among females and males respectively. Interpretation: Prevention of socioeconomic inequalities in cardiovascular disease risk requires a life course approach beginning at the earliest opportunity, especially among females. Funding: The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). KON is supported by a Health Research Board (HRB) of Ireland Investigator Led Award (ILP-PHR-2022-008). JB, GDS and KT work in a unit funded by the UK MRC (MC_UU_00011/1 and MC UU 00011/3) and the University of Bristol. OR is supported by a UKRI Future Leaders Fellowship (MR/S03532X/1). These funding sources had no role in the design and conduct of this study. This publication is the work of the authors and KON will serve as guarantor for the contents of this paper.

Abstract The aim of our study was to assess whether a well-established federal state-wide Stroke Care Pathway delivering high quality stroke care can cope with the COVID-19 pandemic and associated measures to contain the virus spread. The retrospective analysis is based on a prospective, quality-controlled, population-based registry of all stroke patients in the Tyrol, a federal state of Austria and one of the early hot-spots of COVID-19 in Europe. Patient characteristics, pre-hospital management, intra-hospital management and post-hospital were analysed. All residents of the Tyrol suffering ischemic stroke in 2020 (n = 1160) and four pre-COVID-19 years (n = 4321) were evaluated. In 2020, the annual number of stroke patients was the highest in this population-based registry. When local hospitals were overwhelmed with SARS-CoV-2-patients, stroke subjects were temporarily allocated to the comprehensive stroke centre. Stroke severity, quality metrics of stroke management, serious complications, and post-stroke mortality did not differ between 2020 and the four comparator years. Notably, iv. thrombolysis-rate was similar (19.9% versus 17.4%, P = 0.25) and endovascular stroke treatment even better (5.9% versus 3.9%, P = 0.003) but resources for in-patient rehabilitation were limited (25.8% versus 29.8%, P = 0.009). Concluding, a well-established Stroke Care Pathway was able to maintain high-quality acute stroke care even when challenged by a global pandemic.

Physical social contact, such as grooming in primates or touch in humans, is fundamental to create and maintain social bonds. The Brain Opioid Theory of Social Attachment postulates that µ-opioids play a central role in social connection. Accordingly, pharmacological studies in isolated animals indicate that µ-opioid agonists reduce, and µ-opioid antagonists increase distress responses and motivation for social contact. Despite the abundance of animal studies, human evidence is still lacking.Here, we investigated the neurochemical basis of social motivation under stress in healthy human volunteers, following morphine (µ-opioid agonist) or placebo administration. By adopting a translational approach, real physical effort and facial hedonic reactions, together with self-reports of wanting and liking for social touch, were assessed.Preliminary results revealed increased adverse response to stress following morphine administration. In line with animal models and previous evidence in humans, this enhanced stress response led to increased motivation to obtain social touch.

Background Conventional "low-density lipoprotein cholesterol (LDL-C)" assays measure cholesterol content in both low-density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of "LDL-C" and corrected LDL-C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline-recommended LDL-C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from "LDL-C" to obtain corrected LDL-C values (LDL-Ccorr30). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual-patient-data meta-analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow-up). When comparing top versus bottom quartiles, the multivariable-adjusted hazard ratio for cardiovascular disease was significant for "LDL-C" (1.17; 95% CI, 1.05-1.31; P=0.005) but not for LDL-Ccorr30 (1.07; 95% CI, 0.93-1.22; P=0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline-recommended LDL-C categories when using LDL-Ccorr30 was assessed. In "LDL-C" categories of 70 to

Background: To provide updated estimates on SARS-CoV-2 antibody seroprevalence and average antibody titres for Central Europe. Methods: In repeat cross-sectional investigations (1 May 2022 to 9 March 2023) involving 28,768 blood donors in the Federal State of Tyrol, Austria (participation rate: 87.0%), we measured Spike receptor-binding domain (RBD) and Nucleocapsid IgG antibodies (37,065 and 12,645 samples), and estimated monthly seroprevalences and geometric mean titres. Results: Median age of participants was 45.4 years (range 18–70); 43.2% were female. Spike RBD IgG antibody seroprevalence was 96.3% (95% CI: 95.6–96.9%) in May 2022, 97.4% (96.7–98.0%) in December 2022, and 97.9% (96.4–98.8%) in March 2023. Among seropositive participants, geometric mean titres increased from 1400 BAU/mL (95% CI: 1333–1471) in May 2022 to 1821 BAU/mL (1717–1932) in December 2022, and dropped to 1559 BAU/mL (1405–1729) by March 2023. Furthermore, titres differed markedly by vaccination status and history of infection, with being the highest in participants with booster vaccination and prior infection. In autumn 2022, Nucleocapsid IgG antibody seroprevalence ranged from 36.5% (35.0–38.1) in September to 39.2% (37.2–41.2) in December 2022. Conclusion: Seroprevalence of SARS-CoV-2 antibodies in blood donors from Tyrol, Austria, was remarkably stable from May 2022 to March 2023. In contrast, average Spike RBD IgG antibody titres peaked in December 2022.

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC‐CVD (European Prospective Investigation Into Cancer and Nutrition‐Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC‐CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow‐up of 12.6 years (interquartile range, 11.8–13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07–1.12) for stroke, 1.09 (95% CI, 1.06–1.13) for ischemic stroke, 1.10 (95% CI, 1.04–1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08–1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84–1.20) for subarachnoid hemorrhage. When using 2‐sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

Abstract Objective The stability of the transverse expansion in passive self-ligating bracket treatments is a debated topic in orthodontics. However, to date, only 3 reports are available in the literature, with the maximum follow-up of 3 years after the end of therapy. The present study aims to evaluate the stability of orthodontic treatment with self-ligating brackets in a 6-year follow-up period of time. Materials and methods A sample of 56 non-extractive cases (of whom 33 females, mean age 16.9, SD = 9.0 years) consecutively treated with Damon® system was retrospectively selected. All patients received fixed retainers from canine to canine in both arches at the end of treatment, and no removable retainers were provided. The mean values of the transverse intercusp, transverse centroid and transverse lingual distances were evaluated for all teeth from canines to second molars in both arches. Each measure was calculated at four timepoints: before treatment (T0), at the end of treatment (T1), one year after treatment (T2) and six years after treatment (T3). Transverse diameters were measured for all teeth, starting from the canines to the second molars, for a total of 1680 observations, and subsequently compared in order to evaluate intra-treatment and post-treatment modifications. Results There were increases in all transverse dental measurements during active treatment. A statistically significant (p

Lena Tschiderer,1,2 Lisa Seekircher,1 Peter Willeit,1,3 Sanne AE Peters2,4,5 1Institute of Health Economics, Medical University of Innsbruck, Innsbruck, Austria; 2Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; 3Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; 4The George Institute for Global Health, School of Public Health, Imperial College London, London, UK; 5The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, AustraliaCorrespondence: Lena Tschiderer, Institute of Health Economics, Medical University of Innsbruck, Innsbruck, Austria, Tel +43 50 504 26272, Email lena.tschiderer@i-med.ac.atAbstract: Cardiovascular disease is the leading cause of death in women worldwide. Nonetheless, there exist several uncertainties in the prediction, diagnosis, and treatment of cardiovascular disease in women. A cornerstone in the prediction of cardiovascular disease is the implementation of risk scores. A variety of pregnancy- and reproductive-factors have been associated with lower or higher risk of cardiovascular disease. Consequently, the question has been raised, whether these female-specific factors also provide added value to cardiovascular risk prediction. In this review, we provide an overview of the existing literature on sex differences in the association of established cardiovascular risk factors with cardiovascular disease and the relation between female-specific factors and cardiovascular risk. Furthermore, we systematically reviewed the literature for studies that assessed the added value of female-specific factors beyond already established cardiovascular risk factors. Adding female-specific factors to models containing established cardiovascular risk factors has led to little or no significant improvement in the prediction of cardiovascular events. However, analyses primarily relied on data from women aged ≥ 40 years. Future investigations are needed to quantify whether pregnancy-related factors improve cardiovascular risk prediction in young women in order to support adequate treatment of risk factors and enhance prevention of cardiovascular disease in women.Keywords: sex differences, female-specific factors, cardiovascular disease, risk prediction, added value

The second-generation anticonvulsant lamotrigine is widely used in the psychiatric field as a mood stabilizer or antidepressant augmentation therapy. Although particularly older anticonvulsants are known for their potential to cause hypersensitivity syndromes, newer antiepileptic drugs do hold a certain risk as well. Presenting a case of a 32-year-old male inpatient of African ethnicity suffering from a primary severe depressive episode in the course of a recurrent major depressive disorder, we report the occurrence of a rapid-onset drug-induced pneumonitis. Herewith, the interstitial pneumonitis occurred after the initiation of 25 mg lamotrigine as an augmentation therapy. Except for the clear temporal correlation between the administration of lamotrigine and the onset of pneumonitis, we did not reveal any further potentially causal diagnostic hints. Importantly, no relevant genetic variations of metabolizing enzymes or drug interactions resulting in lamotrigine overdosage as a potential cause of toxicity were identified. Our experience with a potentially life-threatening adverse drug reaction shortly after the initiation of the largely well-tolerated lamotrigine suggests a potential side effect under the second-generation anticonvulsant although similar adverse events are deemed to be very rare.

IntroductionMedications which target benzodiazepine (BZD) binding sites of GABAA receptors (GABAARs) have been in widespread use since the nineteen-sixties. They carry labels as anxiolytics, hypnotics or antiepileptics. All benzodiazepines and several nonbenzodiazepine Z-drugs share high affinity binding sites on certain subtypes of GABAA receptors, from which they can be displaced by the clinically used antagonist flumazenil. Additional binding sites exist and overlap in part with sites used by some general anaesthetics and barbiturates. Despite substantial preclinical efforts, it remains unclear which receptor subtypes and ligand features mediate individual drug effects. There is a paucity of literature comparing clinically observed adverse effect liabilities across substances in methodologically coherent ways.MethodsIn order to examine heterogeneity in clinical outcome, we screened the publicly available U.S. FDA adverse event reporting system (FAERS) database for reports of individual compounds and analyzed them for each sex individually with the use of disproportionality analysis. The complementary use of physico-chemical descriptors provides a molecular basis for the analysis of clinical observations of wanted and unwanted drug effects.Results and DiscussionWe found a multifaceted FAERS picture, and suggest that more thorough clinical and pharmacoepidemiologic investigations of the heterogenous side effect profiles for benzodiazepines and Z-drugs are needed. This may lead to more differentiated safety profiles and prescription practice for particular compounds, which in turn could potentially ease side effect burden in everyday clinical practice considerably. From both preclinical literature and pharmacovigilance data, there is converging evidence that this very large class of psychoactive molecules displays a broad range of distinctive unwanted effect profiles - too broad to be explained by the four canonical, so-called “diazepam-sensitive high-affinity interaction sites”. The substance-specific signatures of compound effects may partly be mediated by phenomena such as occupancy of additional binding sites, and/or synergistic interactions with endogenous substances like steroids and endocannabinoids. These in turn drive the wanted and unwanted effects and sex differences of individual compounds.

Background The association between common carotid artery intima‐media thickness (CCA‐IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA‐IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta‐analysis of 20 prospective studies from the Proof‐ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA‐IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA‐IMT was 0.71 mm (SD, 0.17 mm). Over a median follow‐up of 5.9 years (5th–95th percentile, 1.9–19.0 years), 8278 individuals developed first‐ever carotid plaque. We combined study‐specific odds ratios (ORs) for incident carotid plaque using random‐effects meta‐analysis. Baseline CCA‐IMT was approximately log‐linearly associated with the odds of developing carotid plaque. The age‐, sex‐, and trial arm–adjusted OR for carotid plaque per SD higher baseline CCA‐IMT was 1.40 (95% CI, 1.31–1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low‐ and high‐density lipoprotein cholesterol, and lipid‐lowering and antihypertensive medication was 1.34 (95% CI, 1.24–1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29–1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large‐scale individual participant data meta‐analysis demonstrated that CCA‐IMT is associated with the long‐term risk of developing first‐ever carotid plaque, independent of traditional cardiovascular risk factors.

Immunoglobulin M (IgM) autoantibodies to oxidation-specific epitopes (OSEs) can be present at birth and protect against atherosclerosis in experimental models. This study sought to determine whether high titers of IgM titers to OSE (IgM OSE) are associated with a lower risk of acute myocardial infarction (AMI) in humans. IgM to malondialdehyde (MDA)-LDL, phosphocholine-modified BSA, IgM apolipoprotein B100-immune complexes, and a peptide mimotope of MDA were measured within 24 h of first AMI in 4,559 patients and 4,617 age- and sex-matched controls in the Pakistan Risk of Myocardial Infarction Study. Multivariate-adjusted logistic regression was used to estimate odds ratio (OR) and 95% confidence interval for AMI. All four IgM OSEs were lower in AMI versus controls (P < 0.001 for all). Males, smokers and individuals with hypertension and diabetes had lower levels of all four IgM OSE than unaffected individuals (P < 0.001 for all). Compared to the lowest quintile, the highest quintiles of IgM MDA-LDL, phosphocholine-modified BSA, IgM apolipoprotein B100-immune complexes, and MDA mimotope P1 had a lower OR of AMI: OR (95% confidence interval) of 0.67 (0.58–0.77), 0.64 (0.56–0.73), 0.70 (0.61–0.80) and 0.72 (0.62–0.82) (P < 0.001 for all), respectively. Upon the addition of IgM OSE to conventional risk factors, the C-statistic improved by 0.0062 (0.0028–0.0095) and net reclassification by 15.5% (11.4–19.6). These findings demonstrate that IgM OSE provides clinically meaningful information and supports the hypothesis that higher levels of IgM OSE may be protective against AMI.

With ongoing anthropogenic CO _2 emissions, the Greenland ice sheet (GIS) approaches critical thresholds of inevitable, long-term mass loss. Future technologies might be able to efficiently remove CO _2 from the atmosphere and thereby cool down our planet. We explore whether and to what extent a realization of this concept could lead to a regrowth of the GIS once it has partly melted. Using the fully coupled Earth system model of intermediate complexity CLIMBER-X, emission pulses between 0 and 4000 GtC are released into the atmosphere, and after 1 kyr, 2 kyr, and 5 kyr, the atmospheric CO _2 concentration is reduced back to its pre-industrial value. We find that independent of a specific trajectory, once the southern part of the GIS has partly melted with a total mass loss of more than 0.4 m sea level equivalent, regrowth is inhibited. Uncertainties preclude determination of precise thresholds, but model results indicate that cumulative industrial-era emissions approaching 1000–1500 GtC and beyond increasingly risk irreversible mass loss of the GIS. Once this threshold is passed, artificial atmospheric carbon removal would need to be utilised within the next centuries at massive scale. Beyond that, artificial atmospheric carbon removal has limited abilities to avoid long-term mass loss of the GIS. In conclusion, keeping cumulative anthropogenic emissions below 1000–1500 GtC is the only safe way to avoid irreversible mass loss of the GIS.

The newly developed fast Earth system model CLIMBER-X is presented. The climate component of CLIMBER-X consists of a 2.5-D semi-empirical statistical–dynamical atmosphere model, a 3-D frictional–geostrophic ocean model, a dynamic–thermodynamic sea ice model and a land surface model. All the model components are discretized on a regular lat–long grid with a horizontal resolution of 5∘×5∘. The model has a throughput of ∼ 10 000 simulation years per day on a single node with 16 CPUs on a high-performance computer and is designed to simulate the evolution of the Earth system on temporal scales ranging from decades to >100 000 years. A comprehensive evaluation of the model performance for the present day and the historical period shows that CLIMBER-X is capable of realistically reproducing many observed climate characteristics, with results that generally lie within the range of state-of-the-art general circulation models. The analysis of model performance is complemented by a thorough assessment of climate feedbacks and model sensitivities to changes in external forcings and boundary conditions. Limitations and applicability of the model are critically discussed. CLIMBER-X also includes a detailed representation of the global carbon cycle and is coupled to an ice sheet model, which will be described in separate papers. CLIMBER-X is available as open-source code and is expected to be a useful tool for studying past climate changes and for the investigation of the long-term future evolution of the climate.

Abstract Understanding the future fate of the Greenland Ice Sheet (GIS) in the context of anthropogenic CO2 emissions is crucial to predict sea level rise. With the fully coupled Earth system model of intermediate complexity CLIMBER‐X, we study the stability of the GIS and its transient response to CO2 emissions over the next 10 Kyr. Bifurcation points exist at global temperature anomalies of 0.6 and 1.6 K relative to pre‐industrial. For system states in the vicinity of the equilibrium ice volumes corresponding to these temperature anomalies, mass loss rate and sensitivity of mass loss to cumulative CO2 emission peak. These critical ice volumes are crossed for cumulative emissions of 1,000 and 2,500 GtC, which would cause long‐term sea level rise by 1.8 and 6.9 m respectively. In summary, we find tipping of the GIS within the range of the temperature limits of the Paris agreement.

Human behaviour requires flexible arbitration between actions we do out of habit and actions that are directed towards a specific goal. Drugs that target opioid and dopamine receptors are notorious for inducing maladaptive habitual drug consumption; yet, how the opioidergic and dopaminergic neurotransmitter systems contribute to the arbitration between habitual and goal-directed behaviour is poorly understood. By combining pharmacological challenges with a well-established decision-making task and a novel computational model, we show that the administration of the dopamine D2/3 receptor antagonist amisulpride led to an increase in goal-directed or ‘model-based’ relative to habitual or ‘model-free’ behaviour, whereas the non-selective opioid receptor antagonist naltrexone had no appreciable effect. The effect of amisulpride on model-based/model-free behaviour did not scale with drug serum levels in the blood. Furthermore, participants with higher amisulpride serum levels showed higher explorative behaviour. These findings highlight the distinct functional contributions of dopamine and opioid receptors to goal-directed and habitual behaviour and support the notion that even small doses of amisulpride promote flexible application of cognitive control.