Does venous thromboembolism prophylaxis affect the risk of venous thromboembolism and adverse events following primary hip and knee replacement?:A retrospective cohort study

BACKGROUND: The optimum chemical venous thromboembolism (VTE) prophylactic agents following total hip and knee replacement (THR and TKR) remain unknown. NICE recommends multiple agents, including direct oral anticoagulants (DOACs), low-molecular weight heparin (LMWH), and aspirin. We assessed whether VTE prophylaxis affected the risk of VTE and adverse events following primary THR and TKR. MATERIALS AND METHODS: We reviewed 982 elective primary THRs (59%) and TKRs (41%) at a large tertiary centre during 2018. The primary outcome was any VTE (DVT and/or PE) within 90-days. Secondary outcomes were adverse events within 90-days (major bleeding and wound complications). The association between VTE prophylaxis and outcomes was assessed. RESULTS: The overall prevalence of VTE and adverse events were 2.7% (n = 27) and 15.2% (n = 136) respectively. The most common agents used were DOAC ± LMWH (50.7%, n = 498), followed by aspirin ± LMWH (35.5%, n = 349) and LMWH alone (4.7%, n = 46). The risk of VTE (aspirin ± LMWH = 3.7%, DOAC = 2.0%, LMWH = 2.2%) was not significantly different between agents (p = 0.294). The risk of any adverse event was significantly higher (p < 0.001) with aspirin ± LMWH (16.1%; n = 56) and LMWH (28.3%; n = 13) compared with DOACs ± LMWH (7.0%; n = 35) in TKRs only, there was no differences between agents for adverse events in THRs (p = 0.644). CONCLUSIONS: Choice of thromboprophylaxis did not influence the risk of VTE following primary THR and TKR. DOACs (+/− LMWH) were associated with the lowest risk of adverse events. Large multicentre trials are still needed to assess the efficacy and safety of these agents following THR and TKR

Testing the accuracy of radiative cooling approximations in SPH simulations

Hydrodynamical simulations of star formation have stimulated a need to develop fast and robust algorithms for evaluating radiative cooling. Here we undertake a critical evaluation of what is currently a popular method for prescribing cooling in SPH simulations, i.e. the polytropic cooling due originally to Stamatellos et al. This method uses the local density and potential to estimate the column density and optical depth to each particle and then uses these quantities to evaluate an approximate expression for the net radiative cooling. We evaluate the algorithm by considering both spherical and disc-like systems with analytic density and temperature structures. In spherical systems, the total cooling rate computed by the method is within around 20 for the astrophysically relevant case of opacity dominated by ice grains and is correct to within a factor of order unity for a range of opacity laws. In disc geometry, however, the method systematically under-estimates the cooling by a large factor at all heights in the disc. For the self-gravitating disc studied, we find that the method under-estimates the total cooling rate by a factor of 200. This discrepancy may be readily traced to the method's systematic over-estimate of the disc column density and optical depth, since (being based only on the local density and potential) it does not take into account the low column density route for photon escape normal to the disc plane. These results raise an obvious caution about the method's use in disc geometry whenever an accurate cooling rate is required, although we note that there are situations where the discrepancies highlighted above may not significantly affect the global outcome of simulations. Finally, we draw attention to our introduction of an analytic self-gravitating disc structure that may be of use in the calibration of future cooling algorithms.Comment: 10 pages, 8 figures. Accepted for publication in MNRA

Middle to Late Miocene Extremely Rapid Exhumation and Thermal Reequilibration in the Kung Co Rift, Southern Tibet

The Kung Co rift is an approximately NNW striking, WSW dipping normal fault exposed in southern Tibet and is part of an extensive network of active approximately NS striking normal faults exposed across the Tibetan Plateau. Detailed new and published (U-Th)/He zircon and apatite thermochronometric data from the footwall of the early Miocene Kung Co granite provide constraints on the middle Miocene to present-day exhumation history of the footwall to the Kung Co fault. Inverse modeling of thermochronometric data yield age patterns that are interpreted as indicating (1) initiation of normal fault slip at ∼12–13 Ma and rapid exhumation of the footwall between ∼13 and 10 Ma, (2) acceleration of normal fault slip at rates of 21.9–6.9 mm/yr at ∼10 Ma, (3) rapid thermal reequilibration between 10 and 9 Ma, and (4) slow exhumation and/or quiescence from ∼9 Ma to the present day. Hanging glacial valleys in the footwall and fault scarps that cut late Quaternary till and moraine deposits indicate that fault slip continues today. Middle to late Miocene initiation of extension across the Kung Co rift is broadly the same as the documented initiation of EW extension across the south central Tibetan Plateau. Eastward flow of middle or lower crust from beneath Tibet accommodated by northward underthrusting of Indian crust beneath Tibet provides a plausible explanation for the onset of EW extension across the Tibetan Plateau

Agricultural productivity in past societies: toward an empirically informed model for testing cultural evolutionary hypotheses

Agricultural productivity, and its variation in space and time, plays a fundamental role in many theories of human social evolution. However, we often lack systematic information about the productivity of past agricultural systems on a scale large enough to test these theories properly. The effect of climate on crop yields has received a great deal of attention resulting in a range of empirical and process-based models, yet the focus has primarily been on current or future conditions. In this paper, we argue for a “bottom-up” approach that estimates potential productivity based on information about the agricultural practices and technologies used in past societies. Of key theoretical interest is using this information to estimate the carrying high quality historical and archaeological information about past societies in order to infer the temporal and geographic patterns of change in agricultural productivity and potential. We discuss information we need to collect about past agricultural techniques and practices, and introduce a new databank initiative that we have developed for collating the best available historical and archaeological evidence. A key benefit of our approach lies in making explicit the steps in the estimation of past productivities and carrying capacities, and in being able to assess the effects of different modelling assumptions. This is undoubtedly an ambitious task, yet promises to provide important insights into fundamental aspects of past societies, enabling us to test more rigorously key hypotheses about human socio-cultural evolution

Inefficient star formation: The combined effects of magnetic fields and radiative feedback

We investigate the effects of magnetic fields and radiative protostellar feedback on the star formation process using self-gravitating radiation magnetohydrodynamical calculations. We present results from a series of calculations of the collapse of 50 solar mass molecular clouds with various magnetic field strengths and with and without radiative transfer. We find that both magnetic fields and radiation have a dramatic impact on star formation, though the two effects are in many ways complementary. Magnetic fields primarily provide support on large scales to low density gas, whereas radiation is found to strongly suppress small-scale fragmentation by increasing the temperature in the high-density material near the protostars. With strong magnetic fields and radiative feedback the net result is an inefficient star formation process with a star formation rate of ~< 10% per free-fall time that approaches the observed rate, although we have only been able to follow the calculations for ~1/3 of a free-fall time beyond the onset of star formation.Comment: 14 pages, 6 figures, accepted for publication in MNRAS. Movies for all the runs and version with high-res figures available from http://users.monash.edu.au/~dprice/pubs/mclusterRT/ v2: minor changes to match published versio

Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches.

Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds

Making the Case for Accelerated Withdrawal of Aducanumab

The controversial approval in June 2021 by the Food and Drug Administration (FDA) of aducanumab (marketed as Aduhelm), Biogen's monoclonal antibody for patients with Alzheimer's disease, raises significant concerns for the dementia field and drug approval process, considering its lack of adequate evidence for clinical efficacy, safety issues, and cost. On 15 December 2021, an international group of clinicians, basic science experts, psychological and social science researchers, lay people with lived experience of dementia, and advocates for public health met to discuss making a recommendation for whether aducanumab's approval should be withdrawn. Attendees considered arguments both in favor of and in opposition to withdrawal and voted unanimously to recommend that the FDA withdraw its approval for aducanumab and to support the Right Care Alliance's filing of a formal Citizen Petition to this effect

Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury

Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure−activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.Fil: Van Zandt, Michael C.. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Whitehouse, Darren L.. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Golebiowski, Adam. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Ji, Min Koo. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Zhang, Mingbao. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Beckett, R. Paul. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Jagdmann, G. Erik. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Ryder, Todd R.. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Sheeler, Ryan. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Andreoli, Monica. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Conway, Bruce. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Mahboubi, Keyvan. Institutes for Pharmaceutical Discovery; Estados UnidosFil: D’Angelo, Gerard. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Mitschler, Andre. Université de Strasbourg; FranciaFil: Cousido Siah, Alexandra. Université de Strasbourg; FranciaFil: Ruiz, Frances X.. Université de Strasbourg; FranciaFil: Howard, Eduardo Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Université de Strasbourg; FranciaFil: Podjarny, Alberto Daniel. Université de Strasbourg; FranciaFil: Schroeter, Hagen. Mars Incorporated; Estados Unido

Expression and trans-specific polymorphism of self-incompatibility RNases in Coffea (Rubiaceae)

Self-incompatibility (SI) is widespread in the angiosperms, but identifying the biochemical components of SI mechanisms has proven to be difficult in most lineages. Coffea (coffee; Rubiaceae) is a genus of old-world tropical understory trees in which the vast majority of diploid species utilize a mechanism of gametophytic self-incompatibility (GSI). The S-RNase GSI system was one of the first SI mechanisms to be biochemically characterized, and likely represents the ancestral Eudicot condition as evidenced by its functional characterization in both asterid (Solanaceae, Plantaginaceae) and rosid (Rosaceae) lineages. The S-RNase GSI mechanism employs the activity of class III RNase T2 proteins to terminate the growth of "self" pollen tubes. Here, we investigate the mechanism of Coffea GSI and specifically examine the potential for homology to S-RNase GSI by sequencing class III RNase T2 genes in populations of 14 African and Madagascan Coffea species and the closely related self-compatible species Psilanthus ebracteolatus. Phylogenetic analyses of these sequences aligned to a diverse sample of plant RNase T2 genes show that the Coffea genome contains at least three class III RNase T2 genes. Patterns of tissue-specific gene expression identify one of these RNase T2 genes as the putative Coffea S-RNase gene. We show that populations of SI Coffea are remarkably polymorphic for putative S-RNase alleles, and exhibit a persistent pattern of trans-specific polymorphism characteristic of all S-RNase genes previously isolated from GSI Eudicot lineages. We thus conclude that Coffea GSI is most likely homologous to the classic Eudicot S-RNase system, which was retained since the divergence of the Rubiaceae lineage from an ancient SI Eudicot ancestor, nearly 90 million years ago.United States National Science Foundation [0849186]; Society of Systematic Biologists; American Society of Plant Taxonomists; Duke University Graduate Schoolinfo:eu-repo/semantics/publishedVersio