Impaired blood pressure (BP) stabilisation after standing, defined using beat-to-beat measurements, has been shown to predict important health outcomes. We aimed to define the relationship between ...individual classes of antihypertensive agent and BP stabilisation among hypertensive older adults.
Cross-sectional analysis from The Irish Longitudinal Study on Ageing, a cohort study of Irish adults aged 50 years and over. Beat-to-beat BP was recorded in participants undergoing an active stand test. We defined grade 1 hypertension according to European Society of Cardiology criteria (systolic BP SBP 140-159 mmHg ± diastolic BP DBP 90-99 mmHg). Outcomes were: (i) initial orthostatic hypotension (IOH) (SBP drop ≥40 mmHg ± DBP drop ≥20 mmHg within 15 seconds s of standing accompanied by symptoms); (ii) sustained OH (SBP drop ≥20 mmHg ± DBP drop ≥10 mmHg from 60 to 110 s inclusive); (iii) impaired BP stabilisation (SBP drop ≥20 mmHg ± DBP drop ≥10 mmHg at any 10 s interval during the test). Outcomes were assessed using multivariable-adjusted logistic regression.
A total of 536 hypertensive participants were receiving monotherapy with a renin-angiotensin-aldosterone-system inhibitor (n = 317, 59.1%), beta-blocker (n = 89, 16.6%), calcium channel blocker (n = 89, 16.6%) or diuretic (n = 41, 7.6%). A further 783 untreated participants met criteria for grade 1 hypertension. Beta-blockers were associated with increased odds of initial OH (OR 2.05, 95% CI 1.31-3.21) and sustained OH (OR 3.36, 95% CI 1.87-6.03) versus untreated grade 1 hypertension. Multivariable adjustment did not attenuate the results. Impaired BP stabilisation was evident at 20 s (OR 2.59, 95% CI 1.58-4.25) and persisted at 110 s (OR 2.90, 95% CI 1.64-5.11). No association was found between the other agents and any study outcome.
Beta-blocker monotherapy was associated with a >2-fold increased odds of initial OH and a >3-fold increased odds of sustained OH and impaired BP stabilisation, compared to untreated grade 1 hypertension. These findings support existing literature questioning the role of beta-blockers as first line agents for essential hypertension.
Dinosaur fossils from the Middle Jurassic are rare globally, but the Isle of Skye (Scotland, UK) preserves a varied dinosaur record of abundant trace fossils and rare body fossils from this time. ...Here we describe two new tracksites from Rubha nam Brathairean (Brothers' Point) near where the first dinosaur footprint in Scotland was found in the 1980s. These sites were formed in subaerially exposed mudstones of the Lealt Shale Formation of the Great Estuarine Group and record a dynamic, subtropical, coastal margin. These tracksites preserve a wide variety of dinosaur track types, including a novel morphotype for Skye: Deltapodus which has a probable stegosaur trackmaker. Additionally, a wide variety of tridactyl tracks shows evidence of multiple theropods of different sizes and possibly hints at the presence of large-bodied ornithopods. Overall, the new tracksites show the dinosaur fauna of Skye is more diverse than previously recognized and give insight into the early evolution of major dinosaur groups whose Middle Jurassic body fossil records are currently sparse.
A finding of reduced aortic-valve leaflet motion was noted on computed tomography (CT) in a patient who had a stroke after transcatheter aortic-valve replacement (TAVR) during an ongoing clinical ...trial. This finding raised a concern about possible subclinical leaflet thrombosis and prompted further investigation.
We analyzed data obtained from 55 patients in a clinical trial of TAVR and from two single-center registries that included 132 patients who were undergoing either TAVR or surgical aortic-valve bioprosthesis implantation. We obtained four-dimensional, volume-rendered CT scans along with data on anticoagulation and clinical outcomes (including strokes and transient ischemic attacks TIAs).
Reduced leaflet motion was noted on CT in 22 of 55 patients (40%) in the clinical trial and in 17 of 132 patients (13%) in the two registries. Reduced leaflet motion was detected among patients with multiple bioprosthesis types, including transcatheter and surgical bioprostheses. Therapeutic anticoagulation with warfarin, as compared with dual antiplatelet therapy, was associated with a decreased incidence of reduced leaflet motion (0% and 55%, respectively, P=0.01 in the clinical trial; and 0% and 29%, respectively, P=0.04 in the pooled registries). In patients who were reevaluated with follow-up CT, restoration of leaflet motion was noted in all 11 patients who were receiving anticoagulation and in 1 of 10 patients who were not receiving anticoagulation (P<0.001). There was no significant difference in the incidence of stroke or TIA between patients with reduced leaflet motion and those with normal leaflet motion in the clinical trial (2 of 22 patients and 0 of 33 patients, respectively; P=0.16), although in the pooled registries, a significant difference was detected (3 of 17 patients and 1 of 115 patients, respectively; P=0.007).
Reduced aortic-valve leaflet motion was shown in patients with bioprosthetic aortic valves. The condition resolved with therapeutic anticoagulation. The effect of this finding on clinical outcomes including stroke needs further investigation. (Funded by St. Jude Medical and Cedars-Sinai Heart Institute; Portico-IDE ClinicalTrials.gov number, NCT02000115; SAVORY registry, NCT02426307; and RESOLVE registry, NCT02318342.).
Objective
The extended endoscopic approach provides unimpaired visualization and direct access to ventral skull base pathology, but is associated with cerebrospinal fluid (CSF) leak in up to 25% of ...patients. To evaluate the impact of improved surgical techniques and devices to better repair skull base defects, we assessed published surgical outcomes of the extended endoscopic endonasal approach in the last two decades for a well-defined homogenous group of tuberculum sellae and olfactory groove meningioma patients.
Methods
Random-effects meta-analyses were performed for studies published between 2004 (first publications) and April 2020. We evaluated CSF leak as primary outcome. Secondary outcomes were gross total resection, improvement in visual outcomes in those presenting with a deficit, intraoperative arterial injury, and 30-day mortality. For the main analyses, publications were pragmatically grouped based on publication year in three categories: 2004–2010, 2011–2015, and 2016–2020.
Results
We included 29 studies describing 540 patients with tuberculum sellae and 115 with olfactory groove meningioma. The percentage patients with CSF leak dropped over time from 22% (95% CI: 6–43%) in studies published between 2004 and 2010, to 16% (95% CI: 11–23%) between 2011 and 2015, and 4% (95% CI: 1–9%) between 2016 and 2020. Outcomes of gross total resection, visual improvement, intraoperative arterial injury, and 30-day mortality remained stable over time
Conclusions
We report a noticeable decrease in CSF leak over time, which might be attributed to the development and improvement of new closure techniques (e.g., Hadad-Bassagasteguy flap, and gasket seal), refined multilayer repair protocols, and lumbar drain usage.
Pattern-recognition receptors (PRRs) detect molecular signatures of microbes and initiate immune responses to infection. Prototypical PRRs such as Toll-like receptors (TLRs) signal via a conserved ...pathway to induce innate response genes. In contrast, the signaling pathways engaged by other classes of putative PRRs remain ill defined. Here, we demonstrate that the β-glucan receptor Dectin-1, a yeast binding C type lectin known to synergize with TLR2 to induce TNFα and IL-12, can also promote synthesis of IL-2 and IL-10 through phosphorylation of the membrane proximal tyrosine in the cytoplasmic domain and recruitment of Syk kinase.
syk
−/−
dendritic cells (DCs) do not make IL-10 or IL-2 upon yeast stimulation but produce IL-12, indicating that the Dectin-1/Syk and Dectin-1/TLR2 pathways can operate independently. These results identify a novel signaling pathway involved in pattern recognition by C type lectins and suggest a potential role for Syk kinase in regulation of innate immunity.
A number of feed additives are marketed to assist in boosting the pigs' immune system, regulate gut microbiota, and reduce negative impacts of weaning and other environmental challenges. The most ...commonly used feed additives include acidifiers, zinc and copper, prebiotics, direct-fed microbials, yeast products, nucleotides, and plant extracts. Inclusion of pharmacological levels of zinc and copper, certain acidifiers, and several plant extracts have been reported to result in improved pig performance or improved immune function of pigs. It is also possible that use of prebiotics, direct-fed microbials, yeast, and nucleotides may have positive impacts on pig performance, but results have been less consistent and there is a need for more research in this area.
Hydrogenases are valuable model enzymes for sustainable energy conversion approaches using H
2
, but rational utilization of these base-metal biocatalysts requires a detailed understanding of the ...structure and dynamics of their complex active sites. The intrinsic CO and CN
−
ligands of these metalloenzymes represent ideal chromophores for infrared (IR) spectroscopy, but structural and dynamic insight from conventional IR absorption experiments is limited. Here, we apply ultrafast and two-dimensional (2D) IR spectroscopic techniques, for the first time, to study hydrogenases in detail. Using an O
2
-tolerant NiFe hydrogenase as a model system, we demonstrate that IR pump-probe spectroscopy can explore catalytically relevant ligand bonding by accessing high-lying vibrational states. This ultrafast technique also shows that the protein matrix is influential in vibrational relaxation, which may be relevant for energy dissipation from the active site during fast reaction steps. Further insights into the relevance of the active site environment are provided by 2D-IR spectroscopy, which reveals equilibrium dynamics and structural constraints imposed on the H
2
-accepting intermediate of NiFe hydrogenases. Both techniques offer new strategies for uniquely identifying redox-structural states in complex catalytic mixtures
via
vibrational quantum beats and 2D-IR off-diagonal peaks. Together, these findings considerably expand the scope of IR spectroscopy in hydrogenase research, and new perspectives for the characterization of these enzymes and other (bio-)organometallic targets are presented.
A proof-of-concept study on a catalytic NiFe intermediate reveals structural and dynamical details of hydrogenases by ultrafast and two-dimensional infrared spectroscopies.
Meltwater and runoff from glaciers in High Mountain Asia is a vital freshwater resource for one‐fifth of the Earth's population. Between 13% and 36% of the region's glacierized areas exhibit surface ...debris cover and associated supraglacial ponds whose hydrological buffering roles remain unconstrained. We present a high‐resolution meltwater hydrograph from the extensively debris‐covered Khumbu Glacier, Nepal, spanning a 7 month period in 2014. Supraglacial ponds and accompanying debris cover modulate proglacial discharge by acting as transient and evolving reservoirs. Diurnally, the supraglacial pond system may store >23% of observed mean daily discharge, with mean recession constants ranging from 31 to 108 h. Given projections of increased debris cover and supraglacial pond extent across High Mountain Asia, we conclude that runoff regimes may become progressively buffered by the presence of supraglacial reservoirs. Incorporation of these processes is critical to improve predictions of the region's freshwater resource availability and cascading environmental effects downstream.
Key Points
The monsoon season runoff hydrograph from Khumbu Glacier displays progressive changes in diurnal timing and recession characteristics
We propose that observed hydrological behavior results from seasonal evolution of supraglacial ponds and connections
Predicted expansion of debris‐covered areas and pond extents will influence downstream timing, availability, and quality of meltwater in the Himalaya
NAD+-reducing NiFe hydrogenases are valuable biocatalysts for H2-based energy conversion and the regeneration of nucleotide cofactors. While most hydrogenases are sensitive toward O2 and elevated ...temperatures, the soluble NAD+-reducing NiFe hydrogenase from Hydrogenophilus thermoluteolus (HtSH) is O2-tolerant and thermostable. Thus, it represents a promising candidate for biotechnological applications. Here, we have investigated the catalytic activity and active-site structure of native HtSH and variants in which a glutamate residue in the active-site cavity was replaced by glutamine, alanine, and aspartate. Our biochemical, spectroscopic, and theoretical studies reveal that at least two active-site states of oxidized HtSH feature an unusual architecture in which the glutamate acts as a terminal ligand of the active-site nickel. This observation demonstrates that crystallographically observed glutamate coordination represents a native feature of the enzyme. One of these states is diamagnetic and characterized by a very high stretching frequency of an iron-bound active-site CO ligand. Supported by density-functional-theory calculations, we identify this state as a high-valent species with a biologically unprecedented formal Ni(IV) ground state. Detailed insights into its structure and dynamics were obtained by ultrafast and two-dimensional infrared spectroscopy, demonstrating that it represents a conformationally strained state with unusual bond properties. Our data further show that this state is selectively and reversibly formed under oxic conditions, especially upon rapid exposure to high O2 levels. We conclude that the kinetically controlled formation of this six-coordinate high-valent state represents a specific and precisely orchestrated stereoelectronic response toward O2 that could protect the enzyme from oxidative damage.
Pterosaurs were the first vertebrates to evolve flight1,2 and include the largest flying animals in Earth history.3,4 While some of the last-surviving species were the size of airplanes, pterosaurs ...were long thought to be restricted to small body sizes (wingspans ca. <1.8–1.6 m) from their Triassic origins through the Jurassic, before increasing in size when derived long-skulled and short-tailed pterodactyloids lived alongside a diversity of birds in the Cretaceous.5 We report a new spectacularly preserved three-dimensional skeleton from the Middle Jurassic of Scotland, which we assign to a new genus and species: Dearc sgiathanach gen. et sp. nov. Its wingspan is estimated at >2.5 m, and bone histology shows it was a juvenile-subadult still actively growing when it died, making it the largest known Jurassic pterosaur represented by a well-preserved skeleton. A review of fragmentary specimens from the Middle Jurassic of England demonstrates that a diversity of pterosaurs was capable of reaching larger sizes at this time but have hitherto been concealed by a poor fossil record. Phylogenetic analysis places D. sgiathanach in a clade of basal long-tailed non-monofenestratan pterosaurs, in a subclade of larger-bodied species (Angustinaripterini) with elongate skulls convergent in some aspects with pterodactyloids.6 Far from a static prologue to the Cretaceous, the Middle Jurassic was a key interval in pterosaur evolution, in which some non-pterodactyloids diversified and experimented with larger sizes, concurrent with or perhaps earlier than the origin of birds.
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•A new pterosaur genus and species from the Middle Jurassic of Scotland is described•It is represented by a well-preserved fossil skeleton, including the brain endocast•It was not fully grown when it died and would have had a wingspan of >2.5 m•Pterosaurs evolved to a considerably larger size earlier than previously recognized
Jagielska et al. report a fossil pterosaur skeleton from the Middle Jurassic (ca. 167 million years ago) of Scotland, belonging to a new genus and species, Dearc sgiathanach. With a wingspan of over 2.5 m, it was the size of the largest modern-day flying birds and shows that pterosaurs developed to a large size earlier than previously thought.
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