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Efficacy and Safety Analyses of Recombinant Factor VIIa in Severe Post-Partum Hemorrhage.
Get PDFBackground: Despite a range of available treatments, it is still sometimes challenging to treat patients with severe post-partum hemorrhage (sPPH). Objective: This study evaluated the efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 (NCT04723979), OS-2, OS-3, and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligations, arterial embolization, or hysterectomy) and safety (incidence of thromboembolic events (TE) and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa-exposed women only. Results: A total of 446 women exposed to rFVIIa and 1717 non-exposed controls were included. In the RCT, fewer rFVIIa-exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio: 0.11; 95% confidence interval: 0.03-0.35). In OS-1, more rFVIIa-exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio: 2.46; 95% confidence interval: 1.06-5.99). In OS-2, 17% (3/18) of rFVIIa-exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio: 0.33; 95% confidence interval: 0.03-1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa-exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa on the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment
Mechanisms maintaining right ventricular contractility-to-pulmonary arterial elastance ratio in VA ECMO: a retrospective animal data analysis of RV-PA coupling.
Get PDFBACKGROUND
To optimize right ventricular-pulmonary coupling during veno-arterial (VA) ECMO weaning, inotropes, vasopressors and/or vasodilators are used to change right ventricular (RV) function (contractility) and pulmonary artery (PA) elastance (afterload). RV-PA coupling is the ratio between right ventricular contractility and pulmonary vascular elastance and as such, is a measure of optimized crosstalk between ventricle and vasculature. Little is known about the physiology of RV-PA coupling during VA ECMO. This study describes adaptive mechanisms for maintaining RV-PA coupling resulting from changing pre- and afterload conditions in VA ECMO.
METHODS
In 13 pigs, extracorporeal flow was reduced from 4 to 1 L/min at baseline and increased afterload (pulmonary embolism and hypoxic vasoconstriction). Pressure and flow signals estimated right ventricular end-systolic elastance and pulmonary arterial elastance. Linear mixed-effect models estimated the association between conditions and elastance.
RESULTS
At no extracorporeal flow, end-systolic elastance increased from 0.83 [0.66 to 1.00] mmHg/mL at baseline by 0.44 [0.29 to 0.59] mmHg/mL with pulmonary embolism and by 1.36 [1.21 to 1.51] mmHg/mL with hypoxic pulmonary vasoconstriction (p 0.05). Extracorporeal flow did not change coupling (0.0 [- 0.0 to 0.1] per change of 1 L/min, p > 0.05). End-diastolic volume increased with decreasing extracorporeal flow (7.2 [6.6 to 7.8] ml change per 1 L/min, p < 0.001).
CONCLUSIONS
The right ventricle dilates with increased preload and increases its contractility in response to afterload changes to maintain ventricular-arterial coupling during VA extracorporeal membrane oxygenation
Agroforestry in Madagascar: past, present, and future
Get PDFAgroforestry systems promise a high multifunctionality providing cash and subsistence yields as well as other ecosystem services. Such land systems may be particularly promising for smallholders in tropical landscapes due to high labour intensity and productivity on limited land. Focusing on Madagascar, we here describe the history of agroforestry in the country and review the current literature on agroforestry outcomes as well as factors promoting and hindering agroforest establishment and maintenance. From this, we discuss the potential future of agroforestry in Madagascar. Historically, many crops farmed today in agroforestry systems were originally introduced as plantation crops, mostly in the nineteenth century. Since then, people co-opted these crops into mixed agroforestry systems, often focusing on clove, vanilla, coffee, or cocoa in combination with fruit trees or, for clove, with livestock. Other crops are also integrated, but shares are comparatively low. Overall, 27.4% of Malagasy exports are crops typically farmed in agroforestry systems, providing income for at least 500,000 farmers. Outcomes of agroforestry for biodiversity and ecosystem services are commonly researched, showing benefits over annual crops and monocultures. Social-economic outcomes, including yields, are more scarcely researched, but findings point towards financial benefits for smallholder farmers and a sense of community and collective memory. However, findings emphasize that research gaps remain in terms of geographic and crop coverage, also for ecological outcomes. Looking to the future, we highlight the need to overcome hurdles such as land tenure insecurity, financial barriers to implementation, and unstable value chains to scale agroforestry in Madagascar to the benefit of multifunctional land systems and human wellbeing
Transport of dust across the Solar System: Constraints on the spatial origin of individual micrometeorites from cosmic-ray exposure.
Get PDFThe origin of micrometeorites (MMs) from asteroids and comets is well-established, but the relative contribution from these two classes remains poorly resolved. Likewise, determining the precise origin of individual MMs is an open challenge. Here, cosmic-ray exposure ages are used to resolve the spatial origins of 12 MMs collected from urban areas and Antarctica. Their 26Al and 10Be concentration, produced during cosmic-ray irradiation in space, were measured by accelerator mass spectrometry. These data are compared to results from a model simulating the transport and irradiation of the MM precursors in space. This model, for the first time, considers a variety of orbits, precursor particle sizes, compositions and densities and incorporates non-isotropic solar and galactic cosmic-ray flux profiles, depth-dependent production rates, as well as spherical evaporation during atmospheric entry. While the origin for six MMs remains ambiguous, two MMs show a preferential tendency towards an origin in the Inner Solar System (Near Earth Objects to the Asteroid Belt) and four towards an origin in the Outer Solar System (Jupiter Family Comets to the Kuiper Belt). These findings challenge the notion that dust originating from the Outer Solar System is unlikely to survive long-term transport and delivery to the terrestrial planets. This article is part of the theme issue 'Dust in the Solar System and beyond'
Southern Ocean drives multidecadal atmospheric CO2 rise during Heinrich Stadials.
Get PDFThe last glacial period was punctuated by cold intervals in the North Atlantic region that culminated in extensive iceberg discharge events. These cold intervals, known as Heinrich Stadials, are associated with abrupt climate shifts worldwide. Here, we present CO2 measurements from the West Antarctic Ice Sheet Divide ice core across Heinrich Stadials 2 to 5 at decadal-scale resolution. Our results reveal multi-decadal-scale jumps in atmospheric CO2 concentrations within each Heinrich Stadial. The largest magnitude of change (14.0 ± 0.8 ppm within 55 ± 10 y) occurred during Heinrich Stadial 4. Abrupt rises in atmospheric CO2 are concurrent with jumps in atmospheric CH4 and abrupt changes in the water isotopologs in multiple Antarctic ice cores, the latter of which suggest rapid warming of both Antarctica and Southern Ocean vapor source regions. The synchroneity of these rapid shifts points to wind-driven upwelling of relatively warm, carbon-rich waters in the Southern Ocean, likely linked to a poleward intensification of the Southern Hemisphere westerly winds. Using an isotope-enabled atmospheric circulation model, we show that observed changes in Antarctic water isotopologs can be explained by abrupt and widespread Southern Ocean warming. Our work presents evidence for a multi-decadal- to century-scale response of the Southern Ocean to changes in atmospheric circulation, demonstrating the potential for dynamic changes in Southern Ocean biogeochemistry and circulation on human timescales. Furthermore, it suggests that anthropogenic CO2 uptake in the Southern Ocean may weaken with poleward strengthening westerlies today and into the future
Intravenous thrombolysis in patients with recent intake of direct oral anticoagulants: A target trial analysis after the liberalization of institutional guidelines.
No full textINTRODUCTION
This study aimed to report the safety and efficacy of off-label intravenous thrombolysis (IVT) with alteplase after sequentially liberalizing our institutional guidelines allowing IVT for patients under direct oral anticoagulants (DOACs) regardless of plasma levels, time of last intake, and without prior anticoagulation reversal therapy.
PATIENTS AND METHODS
We utilized the target-trial methodology to emulate hypothetical criteria of a randomized controlled trial in our prospective stroke registry. Consecutive DOAC patients (06/2021-11/2023) otherwise qualifying for IVT were included. Safety and efficacy outcomes (symptomatic intracranial hemorrhage [ICH], any radiological ICH, major bleeding, 90-day mortality, 90-day good functional outcome [mRS 0-2 or return to baseline]) were assessed using inverse-probability-weighted regression-adjustment comparing patients with versus without IVT.
RESULTS
Ninety eight patients fulfilled the target-trial criteria. IVT was given in 49/98 (50%) patients at a median of 178 (interquartile range 134-285) min after symptom onset with median DOAC plasma level of 77 ng/ml (15 patients had plasma levels > 100 ng/ml; 25/49 [51%] were treated within 12 h after last DOAC ingestion). Endovascular therapy was more frequent in patients without IVT (73% vs 33%). Symptomatic ICH occurred in 0/49 patients receiving IVT and 2/49 patients without IVT (adjusted difference -2.5%; 95% CI -5.9 to 0.8). The rates of any radiological ICH were comparable. Patients receiving IVT were more likely to have good functional outcomes.
DISCUSSION AND CONCLUSION
After liberalizing our approach for IVT regardless of recent DOAC intake, we did not experience any safety concerns. The association of IVT with better functional outcomes warrants prospective randomized controlled trials
One chiral fingerprint to find them all.
Get PDFMolecular fingerprints are indispensable tools in cheminformatics. However, stereochemistry is generally not considered, which is problematic for large molecules which are almost all chiral. Herein we report MAP4C, a chiral version of our previously reported fingerprint MAP4, which lists MinHashes computed from character strings containing the SMILES of all pairs of circular substructures up to a diameter of four bonds and the shortest topological distance between their central atoms. MAP4C includes the Cahn-Ingold-Prelog (CIP) annotation (R, S, r or s) whenever the chiral atom is the center of a circular substructure, a question mark for undefined stereocenters, and double bond cis-trans information if specified. MAP4C performs slightly better than the achiral MAP4, ECFP and AP fingerprints in non-stereoselective virtual screening benchmarks. Furthermore, MAP4C distinguishes between stereoisomers in chiral molecules from small molecule drugs to large natural products and peptides comprising thousands of diastereomers, with a degree of distinction smaller than between structural isomers and proportional to the number of chirality changes. Due to its excellent performance across diverse molecular classes and its ability to handle stereochemistry, MAP4C is recommended as a generally applicable chiral molecular fingerprint. SCIENTIFIC CONTRIBUTION: The ability of our chiral fingerprint MAP4C to handle stereoisomers from small molecules to large natural products and peptides is unprecedented and opens the way for cheminformatics to include stereochemistry as an important molecular parameter across all fields of molecular design
A matter of age? How age affects the adaptation of lactating dairy cows to virtual fencing.
Get PDFVirtual Fencing (VF) can be a helpful technology in managing herds in pasture-based systems. In VF systems, animals wear a VF-collar using global positioning, and physical boundaries are replaced by virtual ones. The Nofence (Nofence AS, Batnfjordsøra, Norway) collars used in this study emit an acoustic warning when an animal approaches the virtual boundaries, followed by an aversive electrical pulse if the animal does not return to the defined area. The stimuli sequence is repeated up to 3 times if the animal continues to walk forward. Although it has been demonstrated that animals successfully learn to adapt to the system, it is unknown if this adaptation changes with animal age and thus has consequences for VF training and animal welfare. This study compared the ability of younger and older dairy cows to adapt to a VF system and whether age affected activity behavior, milk yield, and animal long-term stress under VF management. The study was conducted on four comparable strip-grazing paddocks. Twenty lactating Holstein-Friesian cows, divided into four groups of five animals each, were equipped with VF collars and pedometers. Groups differed in age: two groups of older cows (> 4 lactations) and two groups of younger ones (first lactation). After a 7-day training, paddock sizes were increased by successively moving the virtual fence during four consecutive grazing periods. Throughout the study, the pedometers recorded daily step count, time spent standing, and time spent lying. For the determination of long-term stress, hair samples were collected on the first and last day of the trial and the hair cortisol content was assessed. Data were analyzed by generalized mixed-effect models. Overall, age had no significant impact on animal responses to VF, but there were interaction effects of time: the number of acoustic warnings in the last period was higher in younger cows (P < 0.001), and the duration of acoustic warnings at training was shorter for older cows (P < 0.01). Moreover, younger cows walked more per day during the training (P < 0.01). Finally, no effects in milk yield or hair cortisol content were detected. In conclusion, all cows, regardless of age, adapted rapidly to the VF system without compromising their welfare according to the indicators measured
Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.
No full textBACKGROUND
Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied.
METHODS
We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death.
RESULTS
A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days.
CONCLUSIONS
Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.)
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