TAVR: nemesis of NOACs?

Data on non-vitamin K antagonist oral anticoagulants (NOACs) in transcatheter aortic valve replacement (TAVR) patients are controversial. In patients without atrial fibrillation (AF), rivaroxaban showed enhanced ischemia and bleeding as compared to standard of care. ENVISAGE showed enhanced bleeding in AF patients as compared to vitamin K antagonist (VKA). Only apixaban was non-inferior but failed superiority regarding bleeding in AF patients after TAVR. One could hypothesize that this might be due to pharmacokinetics of NOACs. Therefore, we compared outcome in rivaroxaban/edoxaban (once-daily) and apixaban (twice-daily) treated patients. 568 patients with indication for permanent oral anticoagulation due to AF undergoing TAVR were analyzed via inverse probability of treatment weighting. Valve academic research consortium complications during 30-day follow-up were assessed. Bleeding complications were similar in once-daily and twice-daily NOACs (major: 22 (7.5%) vs. 14 (5.3%), p = 0.285; minor: 66 (22.4%) vs. 46 (17.4%), p = 0.133). Complications did not change when splitting the cohort in the different agents apixaban, rivaroxaban and edoxaban. These findings remained robust after multivariate analysis. In summary, twice-daily and once-daily NOACs did not differ regarding bleeding complications in a hypothesis generating real-world cohort of TAVR patients with AF.

Thermal optima of gross primary productivity are closely aligned with mean air temperatures across Australian wooded ecosystems.

Gross primary productivity (GPP) of wooded ecosystems (forests and savannas) is central to the global carbon cycle, comprising 67%-75% of total global terrestrial GPP. Climate change may alter this flux by increasing the frequency of temperatures beyond the thermal optimum of GPP (Topt ). We examined the relationship between GPP and air temperature (Ta) in 17 wooded ecosystems dominated by a single plant functional type (broadleaf evergreen trees) occurring over a broad climatic gradient encompassing five ecoregions across Australia ranging from tropical in the north to Mediterranean and temperate in the south. We applied a novel boundary-line analysis to eddy covariance flux observations to (a) derive ecosystem GPP-Ta relationships and Topt (including seasonal analyses for five tropical savannas); (b) quantitatively and qualitatively assess GPP-Ta relationships within and among ecoregions; (c) examine the relationship between Topt and mean daytime air temperature (MDTa) across all ecosystems; and (d) examine how down-welling short-wave radiation (Fsd) and vapour pressure deficit (VPD) influence the GPP-Ta relationship. GPP-Ta relationships were convex parabolas with narrow curves in tropical forests, tropical savannas (wet season), and temperate forests, and wider curves in temperate woodlands, Mediterranean woodlands, and tropical savannas (dry season). Ecosystem Topt ranged from 15℃ (temperate forest) to 32℃ (tropical savanna-wet and dry seasons). The shape of GPP-Ta curves was largely determined by daytime Ta range, MDTa, and maximum GPP with the upslope influenced by Fsd and the downslope influenced by VPD. Across all ecosystems, there was a strong positive linear relationship between Topt and MDTa (Adjusted R2 : 0.81; Slope: 1.08) with Topt exceeding MDTa by >1℃ at all but two sites. We conclude that ecosystem GPP has adjusted to local MDTa within Australian broadleaf evergreen forests and that GPP is buffered against small Ta increases in the majority of these ecosystems.

Enhanced Platelet Reactivity under Aspirin Medication and Major Adverse Cardiac and Cerebrovascular Events in Patients with Coronary Artery Disease.

Aspirin is indispensable in secondary prevention of ischemic events in patients with coronary artery disease (CAD). However, insufficient platelet inhibition despite aspirin medication is frequent. This is referred to as high on-treatment platelet reactivity (HTPR). Nevertheless, if this is associated with clinical outcome instead of only laboratory phenomenon remains unclear so far. In this study, we test whether patients with ischemic events have higher platelet reactivity despite aspirin medication than patients without ischemic events. In this prospective study of 72 CAD patients, we determined pharmacodynamic response to aspirin by arachidonic acid induced aggregation via light-transmission aggregometry and expressed as maximum of aggregation (MoA). During a mean follow-up duration of 3.2 years, major adverse cardiac and cerebrovascular events (MACCE), mortality, non-ST-elevation myocardial infarction (NSTEMI), and stroke were assessed as endpoints via yearly telephone interviews with the treating physician of the patients. Patients who suffered from MACCE, death, and NSTEMI had a significantly higher MoA than those without (MACCE: 5.4 vs. 16.4%, p < 0.05; death: 5.6 vs. 16.8%, p < 0.05; NSTEMI: 1.8 vs. 21%, p < 0.001). MoA did not differ with regard to the occurrence of stroke (10.1 vs. 14.9%, p = 0.59). Patients with MACCE, death, and NSTEMI show enhanced platelet reactivity despite aspirin medication as compared to patients without ischemic events. Hence, insufficient response to aspirin medication should be regarded as risk factor for ischemic events in CAD patients. Further trials are needed to assess options to overcome HTPR to aspirin.

The Myth of the Stupid Believer: The Negative Religiousness-IQ Nexus is Not on General Intelligence (g) and is Likely a Product of the Relations Between IQ and Autism Spectrum Traits.

Numerous studies have found a negative relationship between religiousness and IQ. It is in the region of - 0.2, according to meta-analyses. The reasons for this relationship are, however, unknown. It has been suggested that higher intelligence leads to greater attraction to science, or that it helps to override evolved cognitive dispositions such as for religiousness. Either way, such explanations assume that the religion-IQ nexus is on general intelligence (g), rather than some subset of specialized cognitive abilities. In other words, they assume it is a Jensen effect. Two large datasets comparing groups with different levels of religiousness show that their IQ differences are not on g and must, therefore, be attributed to specialized abilities. An analysis of the specialized abilities on which the religious and non-religious groups differ reveals no clear pattern. We cautiously suggest that this may be explicable in terms of autism spectrum disorder traits among people with high IQ scores, because such traits are negatively associated with religiousness.

Heparin dosing in patients with Impella-supported cardiogenic shock.

BACKGROUND: Impella™ is increasingly used in cardiogenic shock. However, thromboembolic and bleeding events are frequent during percutaneous mechanical circulatory support (pMCS). OBJECTIVE: Therefore, we aimed to explore the optimal anticoagulation regime for pMCS to prevent thromboembolism and bleedings. METHODS: This hypothesis-generating multi-center cohort study investigated 170 patients with left-Impella™ support. We (A) compared bleeding/thrombotic events in two centers with therapeutic range (TR-aPTT) activated partial thromboplastin time (60-80s) and (B) compared events of these centers with one center with intermediate range aPTT (40-60s). RESULTS: After matching, there were no differences in patients' characteristics. In centers aiming at TR-aPTT, major bleeding was numerically lower with aPTT <60s within 48 h of left-Impella™ support, versus patients that achieved the aimed aPTT of ≥60s [aPTT ≥60s: 22 (37.3%) vs. aPTT<60s 14 (23.7%); Hazard ratio [HR], 0.62 (95%) CI, 0.28-1.38; p = 0.234]. Major cardiovascular and cerebrovascular adverse events (MACCE) did not differ between groups. In comparison of centers, TR-aPTT strategy showed higher major bleeding rates [TR: 8 (47.1%) vs. intermediate range: 1 (5.9%); HR, 0.06 (95%) CI, 0.01-0.45; p = 0.006]. MACCE were lower in the intermediate range aPTT group as well [TR 12 (70.6%) vs. intermediate range 5 (29.4%) HR, 0.32 (95%) CI, 0.11-0.92; p = 0.034]. CONCLUSION: This pilot analysis showed that lowering UFH-targets in left-Impella™ supported CS patients seems to be a safe and promising strategy for reducing major bleedings without increasing MACCE. This needs to be validated in larger, randomized clinical trials.

Revealing concealed cardioprotection by platelet Mfsd2b-released S1P in human and murine myocardial infarction.

Antiplatelet medication is standard of care in acute myocardial infarction (AMI). However, it may have obscured beneficial properties of the activated platelet secretome. We identify platelets as major source of a sphingosine-1-phosphate (S1P) burst during AMI, and find its magnitude to favorably associate with cardiovascular mortality and infarct size in STEMI patients over 12 months. Experimentally, administration of supernatant from activated platelets reduces infarct size in murine AMI, which is blunted in platelets deficient for S1P export (Mfsd2b) or production (Sphk1) and in mice deficient for cardiomyocyte S1P receptor 1 (S1P1). Our study reveals an exploitable therapeutic window in antiplatelet therapy in AMI as the GPIIb/IIIa antagonist tirofiban preserves S1P release and cardioprotection, whereas the P2Y12 antagonist cangrelor does not. Here, we report that platelet-mediated intrinsic cardioprotection is an exciting therapeutic paradigm reaching beyond AMI, the benefits of which may need to be considered in all antiplatelet therapies.

Tapping into the physiological responses to mistletoe infection during heat and drought stress.

Mistletoes are important co-contributors to tree mortality globally, particularly during droughts. In Australia, mistletoe distributions are expanding in temperate woodlands, while their hosts have experienced unprecedented heat and drought stress in recent years. We investigated whether the excessive water use of mistletoes increased the probability of xylem emboli in a mature woodland during the recent record drought that was compounded by multiple heatwaves. We continuously recorded transpiration ($T_{SLA}$) of infected and uninfected branches from two eucalypt species over two summers, monitored stem and leaf water potentials ($\Psi $) and used hydraulic vulnerability curves to estimate percent loss in conductivity (PLC) for each species. Variations in weather (vapor pressure deficit, photosynthetically active radiation, soil water content), host species and % mistletoe foliage explained 78% of hourly $T_{SLA}$. While mistletoe acted as an uncontrollable sink for water in the host even during typical summer days, daily $T_{SLA}$ increased up to 4-fold in infected branches on hot days, highlighting the previously overlooked importance of temperature stress in amplifying water loss in mistletoes. The increased water use of mistletoes resulted in significantly decreased host $\Psi _{\rm{leaf}}$ and $\Psi _{\rm{trunk}}$. It further translated to an estimated increase of up to 11% PLC for infected hosts, confirming greater hydraulic dysfunction of infected trees that place them at higher risk of hydraulic failure. However, uninfected branches of Eucalyptus fibrosa F.Muell. had much tighter controls on water loss than uninfected branches of Eucalyptus moluccana Roxb., which shifted the risk of hydraulic failure towards an increased risk of carbon starvation for E. fibrosa. The contrasting mechanistic responses to heat and drought stress between both co-occurring species demonstrates the complexity of host-parasite interactions and highlights the challenge in predicting species-specific responses to biotic agents in a warmer and drier climate.

Global application of an unoccupied aerial vehicle photogrammetry protocol for predicting aboveground biomass in non-forest ecosystems.

Non-forest ecosystems, dominated by shrubs, grasses and herbaceous plants, provide ecosystem services including carbon sequestration and forage for grazing, and are highly sensitive to climatic changes. Yet these ecosystems are poorly represented in remotely sensed biomass products and are undersampled by in situ monitoring. Current global change threats emphasize the need for new tools to capture biomass change in non-forest ecosystems at appropriate scales. Here we developed and deployed a new protocol for photogrammetric height using unoccupied aerial vehicle (UAV) images to test its capability for delivering standardized measurements of biomass across a globally distributed field experiment. We assessed whether canopy height inferred from UAV photogrammetry allows the prediction of aboveground biomass (AGB) across low-stature plant species by conducting 38 photogrammetric surveys over 741 harvested plots to sample 50 species. We found mean canopy height was strongly predictive of AGB across species, with a median adjusted R 2 of 0.87 (ranging from 0.46 to 0.99) and median prediction error from leave-one-out cross-validation of 3.9%. Biomass per-unit-of-height was similar within but different among, plant functional types. We found that photogrammetric reconstructions of canopy height were sensitive to wind speed but not sun elevation during surveys. We demonstrated that our photogrammetric approach produced generalizable measurements across growth forms and environmental settings and yielded accuracies as good as those obtained from in situ approaches. We demonstrate that using a standardized approach for UAV photogrammetry can deliver accurate AGB estimates across a wide range of dynamic and heterogeneous ecosystems. Many academic and land management institutions have the technical capacity to deploy these approaches over extents of 1-10 ha-1. Photogrammetric approaches could provide much-needed information required to calibrate and validate the vegetation models and satellite-derived biomass products that are essential to understand vulnerable and understudied non-forested ecosystems around the globe.

Systemization of a pharmacy technician career ladder in a multi-hospital system.

Purpose: Hospital consolidation into larger, systemized health systems has enabled system-wide standardization of promotion processes, including pharmacy technician career ladders. However, whether system standardization affects the job satisfaction or outcomes of pharmacy technicians is unknown. The purpose of this project was to assess pharmacy technician perceptions and outcomes after systemization of a pharmacy technician career ladder. Methods: Pharmacy technician satisfaction scores and outcomes (promotion and turnover rates) were assessed in an eight-hospital health system before and after systemization of a pharmacy technician career ladder. Results: Two hundred and forty-nine pharmacy technicians were employed during the pre-intervention (n = 104) and post-intervention (n = 145) time periods. One hundred and twenty-three of 145 (84.83%) pharmacy technicians completed a job satisfaction survey after implementation of the system-wide technician career ladder. Overall satisfaction for the career ladder averaged 3.8 ± 0.61 or between neutral to positive satisfaction. There was no difference in total satisfaction regardless of teaching (3.8 ± 0.59) or community hospital (3.8 ± 0.63) location (p = 0.53) or stratifying by Pharmacy Technician status. A total of 50 pharmacy technicians were hired during the study period, either during the pre-implementation (n = 36) or post-implementation (n = 14) time periods. Time to the first promotion averaged 1.73 ± 1.00 years in the pre-implementation period and 1.36 ± 0.55 years in the post-implementation period (p = 0.20). Technician voluntary turnover was similar between the time periods. Conclusion: In conclusion, the standardization of a systems-level pharmacy technician promotion ladder from a single hospital to a systems-level was associated with positive job satisfaction and similar promotions and turnover rates as the historic, single hospital-based promotion ladder.

Platelet reactivity is higher in e-cigarette vaping as compared to traditional smoking.

INTRODUCTION: Vaping emerges as alternative to standard tobacco smoking. However, there is evidence for critical cardiovascular, gastrointestinal and respiratory side effects. Nevertheless, long-term vaping effects on thrombocyte reactivity have not been investigated. Therefore, we investigated the influence of vaping on thrombocyte reactivity in comparison to standard smoking and non-smoking. METHODS: Platelet function was measured by Multiplate Impedance Aggregometry as area under the curve (AUC). Smoking habits and characteristics were assessed by questionnaire. Results were analyzed using inverse probability of treatment weighting (IPTW) and conventional t-tests to test for robustness. RESULTS: After IPTW adjustment, participants in all groups were balanced by age, gender, body height and weight. Collagen-induced aggregation was higher in vapers compared to non-smokers (non-smokers 52.55 ± 23.97 vs. vapers 66.63 ± 18.96 AUC, p = 0.002) and to smokers (vapers vs. smokers 49.50 ± 26.05 AUC, p < 0.0001). ADP-induced aggregation in vapers was higher compared to non-smokers (non-smokers 33.16 ± 16.61 vs. vapers 45.27 ± 18.67 AUC, p = 0.001) and was numerically increased compared to smokers (vapers vs. smokers 40.09 ± 19.80 AUC, p = 0.08). These findings remained robust in t-test analysis. CONCLUSION: This study provides first evidence that vaping leads to enhanced platelet reactivity compared to standard smoking and non-smoking. This suggests health effects of vaping might be more severe than previously assumed. Whether this effect translates to clinical outcome with a higher incidence of major cardiovascular events, should be evaluated in large-scaled clinical studies.

Excess Mortality in Aspirin and Dipyrone (Metamizole) Co-Medicated in Patients With Cardiovascular Disease: A Nationwide Study.

Background Pain is a major issue in our aging society. Dipyrone (metamizole) is one of the most frequently used analgesics. Additionally, it has been shown to impair pharmacodynamic response to aspirin as measured by platelet function tests. However, it is not known how this laboratory effect translates to clinical outcome. Methods and Results We conducted a nationwide analysis of a health insurance database in Germany comprising 9.2 million patients. All patients with a cardiovascular event in 2014 and subsequent secondary prevention with aspirin were followed up for 36 months. Inverse probability of treatment weighting analysis was conducted to investigate the rate of mortality, myocardial infarction, and stroke/transient ischemic attack between patients on aspirin-dipyrone co-medication compared with aspirin-alone medication. Permanent aspirin-alone medication was given to 26,200 patients, and 5946 patients received aspirin-dipyrone co-medication. In the inverse probability of treatment weighted sample, excess mortality in aspirin-dipyrone co-medicated patients was observed (15.6% in aspirin-only group versus 24.4% in the co-medicated group, hazard ratio [HR], 1.66 [95% CI, 1.56-1.76], P<0.0001). Myocardial infarction and stroke/transient ischemic attack were increased as well (myocardial infarction: 1370 [5.2%] versus 355 [5.9%] in aspirin-only and co-medicated groups, respectively; HR, 1.18 [95% CI, 1.05-1.32]; P=0.0066, relative risk [RR], 1.14; number needed to harm, 140. Stroke/transient ischemic attack, 1901 [7.3%] versus 506 [8.5%] in aspirin-only and co-medicated groups, respectively; HR, 1.22 [95% CI, 1.11-1.35]; P<0.0001, RR, 1.17, number needed to harm, 82). Conclusions In this observational, nationwide analysis, aspirin and dipyrone co-medication was associated with excess mortality. This was in part driven by ischemic events (myocardial infarction and stroke), which occurred more frequently in co-medicated patients as well. Hence, dipyrone should be used with caution in aspirin-treated patients for secondary prevention.

Using a paired tower approach and remote sensing to assess carbon sequestration and energy distribution in a heterogeneous sclerophyll forest.

The critically endangered Cumberland Plain woodland within the greater Sydney metropolitan area hosts a dwindling refuge for melaleuca trees, an integral part of Australia's native vegetation. Despite their high carbon stocks, melaleucas have not explicitly been targeted for studies assessing their carbon sequestration potential, and especially little is known about their energy cycling or their response to increasing climate stress, precluding a holistic assessment of the resilience of Australia's forests to climate change. To improve our understanding of the role of melaleuca forest responses to climate stress, we combined forest inventory and airborne LiDAR data to identify species distribution and associated variations in forest structure, and deployed flux towers in a melaleuca-dominated (AU-Mel) and in a eucalypt-dominated (AU-Cum) stand to simultaneously monitor carbon and energy fluxes under typical growing conditions, as well as during periods with high atmospheric demand and low soil water content. We discovered that the species distribution at our study site affected the vertical vegetation structure, leading to differences in canopy coverage (75% at AU-Cum vs. 84% at AU-Mel) and plant area index (2.1 m2 m-2 at AU-Cum vs. 2.6 m2 m-2 at AU-Mel) that resulted in a heterogeneous forest landscape. Furthermore, we identified that both stands had comparable net daytime carbon exchange and sensible heat flux, whereas daytime latent heat flux (115.8 W m-2 at AU-Cum vs 119.4 W m-2 at AU-Mel, respectively) was higher at the melaleuca stand, contributing to a 0.3 °C decrease in air temperature and reduced vapor pressure deficit above the melaleuca canopy. However, increased canopy conductance and higher latent heat flux during moderate VPD or when soil moisture was low indicated a lack of water preservation at the melaleuca stand, highlighting the potential for increased vulnerability of melaleucas to projected hotter and drier future climates.

Spatio-temporal transpiration patterns reflect vegetation structure in complex upland terrain.

Topography exerts control on eco-hydrologic processes via alteration of energy inputs due to slope angle and orientation. Further, water availability varies with drainage position in response to topographic water redistribution and the catena effect on soil depth and thus soil water storage capacity. Our understanding of the spatio-temporal dynamics and drivers of transpiration patterns in complex terrain is still limited by lacking knowledge of how systematic interactions of energy and moisture patterns shape ecosystem state and water fluxes and adaptation of the vegetation to these patterns. To untangle the effects of slope orientation and hillslope position on forest structure and transpiration patterns, we measured forest structure, sap flux, soil moisture, throughfall and incoming shortwave radiation along two downslope transects in a forested head water catchment in south-east Australia. Our plot locations controlled for three systematically varying drainage position levels (topographic wetness index: 5.0, 6.5 and 8.0) and two levels of energy input (aridity index: 1.2 and 1.8). Vegetation patterns were generally stronger related to drainage position than slope orientation, whereas sap velocity variations were less pronounced. However, in combination with stand sapwood area, consistent spatio-temporal transpiration patterns emerged in relation to landscape position, where slope orientation was the primary and drainage position the secondary controlling factor. On short temporal scales, radiation and vapor pressure deficit were most important in regulating transpiration rates, whereas soil water limitation only occurred on shallow soils during summer. The importance of stand structural parameters increased on longer time scales, indicating optimization of vegetation in response to the long-term hydro-climatic conditions at a given landscape position. Thus, vegetation patterns can be conceptualized as a 'time-integrated' predictor variable that captures large fractions of other factors contributing to transpiration patterns.