Pharmacokinetics of Tranexamic Acid (TXA) Delivered by Expeditious Routes in a Swine Model of Polytrauma and Hemorrhagic Shock.

OBJECTIVE: Hemorrhage is the leading cause of preventable death in civilian trauma centers and on the battlefield. One of the emerging treatment options for hemorrhage in austere environments is tranexamic acid (TXA). However, the landscape is not amenable to the current delivery standard. This study compared the pharmacokinetics of TXA via a standard 10-minute intravenous infusion (IV infusion), intravenous rapid push over 10 s (IV push), and intramuscular injection (IM) in a swine polytrauma and hemorrhagic shock model (trauma group) compared to uninjured controls (control group). METHODS: Thirty swine were randomized to the trauma or control group. Following anesthesia, the trauma group experienced a simulated blast injury and 40% controlled hemorrhage. Subjects in both groups were then randomized to receive 1 g/10 mL TXA via IV infusion, IV push, or IM. Animals were monitored for four hours with serial blood sampling. Serum TXA concentrations were measured by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and analyzed. RESULTS: The time to maximum TXA concentration (Tmax) was not affected by trauma in IV infusion or IV push, but was affected in the IM administration with Tmax significantly slower than the control group (p = 0.016). The minimum effective serum concentration of TXA (Ceff, 10 µg/mL) was reached in less than one minute with IV infusion and instantaneously with IV push. Despite lower bioavailability, the time to reach Ceff (Teff) was achieved via IM administration in less than 10 min for both groups (6.4 min trauma vs. 2.1 min control). CONCLUSIONS: In austere prehospital environments, an alternative to intravenous infusion of a life-saving medication is desired. Administration of TXA via all three methods reached the level needed to cause substantial inhibition of fibrinolysis within 10 min. The IV push method showed similar pharmacokinetics to IV infusion of TXA but can be delivered quickly without sacrificing an access site for 10 min.

Publication bias impacts on effect size, statistical power, and magnitude (Type M) and sign (Type S) errors in ecology and evolutionary biology.

Collaborative efforts to directly replicate empirical studies in the medical and social sciences have revealed alarmingly low rates of replicability, a phenomenon dubbed the 'replication crisis'. Poor replicability has spurred cultural changes targeted at improving reliability in these disciplines. Given the absence of equivalent replication projects in ecology and evolutionary biology, two inter-related indicators offer the opportunity to retrospectively assess replicability: publication bias and statistical power. This registered report assesses the prevalence and severity of small-study (i.e., smaller studies reporting larger effect sizes) and decline effects (i.e., effect sizes decreasing over time) across ecology and evolutionary biology using 87 meta-analyses comprising 4,250 primary studies and 17,638 effect sizes. Further, we estimate how publication bias might distort the estimation of effect sizes, statistical power, and errors in magnitude (Type M or exaggeration ratio) and sign (Type S). We show strong evidence for the pervasiveness of both small-study and decline effects in ecology and evolution. There was widespread prevalence of publication bias that resulted in meta-analytic means being over-estimated by (at least) 0.12 standard deviations. The prevalence of publication bias distorted confidence in meta-analytic results, with 66% of initially statistically significant meta-analytic means becoming non-significant after correcting for publication bias. Ecological and evolutionary studies consistently had low statistical power (15%) with a 4-fold exaggeration of effects on average (Type M error rates = 4.4). Notably, publication bias reduced power from 23% to 15% and increased type M error rates from 2.7 to 4.4 because it creates a non-random sample of effect size evidence. The sign errors of effect sizes (Type S error) increased from 5% to 8% because of publication bias. Our research provides clear evidence that many published ecological and evolutionary findings are inflated. Our results highlight the importance of designing high-power empirical studies (e.g., via collaborative team science), promoting and encouraging replication studies, testing and correcting for publication bias in meta-analyses, and adopting open and transparent research practices, such as (pre)registration, data- and code-sharing, and transparent reporting.

Towards open, reliable, and transparent ecology and evolutionary biology.

Unreliable research programmes waste funds, time, and even the lives of the organisms we seek to help and understand. Reducing this waste and increasing the value of scientific evidence require changing the actions of both individual researchers and the institutions they depend on for employment and promotion. While ecologists and evolutionary biologists have somewhat improved research transparency over the past decade (e.g. more data sharing), major obstacles remain. In this commentary, we lift our gaze to the horizon to imagine how researchers and institutions can clear the path towards more credible and effective research programmes.

Recent Developments in C-H Activation for Materials Science in the Center for Selective C-H Activation.

Abstract: Organic electronics is a rapidly growing field driven in large part by the synthesis of ∏-conjugated molecules and polymers. Traditional aryl cross-coupling reactions such as the Stille and Suzuki have been used extensively in the synthesis of ∏-conjugated molecules and polymers, but the synthesis of intermediates necessary for traditional cross-couplings can include multiple steps with toxic and hazardous reagents. Direct arylation through C-H bond activation has the potential to reduce the number of steps and hazards while being more atom-economical. Within the Center for Selective C-H Functionalization (CCHF), we have been developing C-H activation methodology for the synthesis of ∏-conjugated materials of interest, including direct arylation of difficult-to-functionalize electron acceptor intermediates and living polymerization of ∏-conjugated polymers through C-H activation.

Rapid, Low Temperature Formation of Imine-Linked Covalent Organic Frameworks Catalyzed by Metal Triflates.

Imine-linked two-dimensional covalent organic frameworks (2D COFs) are crystalline polymer networks with enhanced stability compared to boronate ester-linked systems and with broad monomer scope. They are traditionally prepared by condensing polyfunctional aldehydes and amines at elevated temperature in a mixture of organic solvents and aqueous CH3CO2H, which catalyzes imine formation and exchange. Here we employ metal triflates, which are water-tolerant Lewis acids, to accelerate 2D imine-linked COF synthesis and improve their materials quality. Low catalyst loadings provide crystalline polymer networks in nearly quantitative yields. These conditions are demonstrated for several COFs, including heteroatom-containing systems of interest for optoelectronic applications.

The expression of hypoxia-inducible factor-1α gene is not affected by low-oxygen conditions in yellow perch (Perca flavescens) juveniles.

Hypoxia can affect various fish populations, including yellow perch Perca flavescens, which is an economically and ecologically important species in Lake Erie, a freshwater system that often experiences hypoxia in the hypolimnetic part of the lake. Fish, similarly to mammals, possess molecular oxygen sensor-hypoxia-inducible factor-1 (HIF-1), a transcription factor that can affect expression of many downstream genes related to animal growth and locomotion, protein synthesis, as well as ATP and amino acid metabolism. HIF-1 is a heterodimer, which consists of two subunits: oxygen-sensitive and oxygen-insensitive subunits, α and ß, respectively. In this study, we report first on the molecular cloning and sequencing of P. flavescens HIF-1α. The full-length complementary DNA (cDNA) was isolated and submitted to the GenBank with accession number KT783483. It consists of 3529 base pairs (bp) carrying a single open-reading frame that encompasses 2250 bp of the coding region, 247 bp of the 5' untranslated region (UTR), and 1032 bp of the 3' UTR. The "de novo" prediction of the 3D structure of HIF-1α protein, which consists of 749 amino acids, is presented, too. We then utilized One-Step Taqman® real-time RT-PCR technology to monitor changes in HIF-1α messenger RNA (mRNA) copies in response to chronic hypoxic stress. An experiment was conducted using 14-day post-swim-up stage yellow perch larvae with uninflated swim bladders. This experiment included three treatment groups: hypoxia, mid-hypoxia, and normoxia, in four replicates (four tanks per treatment) with the following dissolved oxygen levels: 3, 4, and >7 mg O2/L, respectively. At the end (2 weeks) and in the middle (1 week) of the experiment, fish from each tank were sampled for body measurements and molecular biology analysis. The results showed no differences in survival (∼90%) between treatment groups. Oxygen concentration was lowered to 3.02 ± 0.15 (mean ± SE) mg O2/L with no adverse effect on fish survival. The highest growth rate was observed in the normoxic group. A similar trend was observed with fish body length. The growth rate of fish declined with decreasing water-dissolved oxygen. The number of HIF-1α mRNA copies was not significantly different between hypoxic, mid-hypoxic, and normoxic conditions, and this was true for fish obtained in the middle and at the end of the experiment. Graphical abstract.

High-Performance Electron Acceptor with Thienyl Side Chains for Organic Photovoltaics.

We develop an efficient fused-ring electron acceptor (ITIC-Th) based on indacenodithieno[3,2-b]thiophene core and thienyl side-chains for organic solar cells (OSCs). Relative to its counterpart with phenyl side-chains (ITIC), ITIC-Th shows lower energy levels (ITIC-Th: HOMO = -5.66 eV, LUMO = -3.93 eV; ITIC: HOMO = -5.48 eV, LUMO = -3.83 eV) due to the σ-inductive effect of thienyl side-chains, which can match with high-performance narrow-band-gap polymer donors and wide-band-gap polymer donors. ITIC-Th has higher electron mobility (6.1 × 10(-4) cm(2) V(-1) s(-1)) than ITIC (2.6 × 10(-4) cm(2) V(-1) s(-1)) due to enhanced intermolecular interaction induced by sulfur-sulfur interaction. We fabricate OSCs by blending ITIC-Th acceptor with two different low-band-gap and wide-band-gap polymer donors. In one case, a power conversion efficiency of 9.6% was observed, which rivals some of the highest efficiencies for single junction OSCs based on fullerene acceptors.

Facile Incorporation of Pd(PPh3)2Hal Substituents into Polymethines, Merocyanines, and Perylene Diimides as a Means of Suppressing Intermolecular Interactions.

Compounds with polarizable π systems that are susceptible to attack with nucleophiles at C-Hal (Hal = Cl, Br) bonds react with Pd(PPh3)4 to yield net oxidative addition. X-ray structures show that the resulting Pd(PPh3)2Hal groups greatly reduce intermolecular π-π interactions. The Pd-functionalized dyes generally exhibit solution-like absorption spectra in films, whereas their Hal analogues exhibit features attributable to aggregation.

C-H-Activated Direct Arylation of Strong Benzothiadiazole and Quinoxaline-Based Electron Acceptors.

Electron acceptors are important components of π-conjugated materials, but the strong electron-withdrawing properties of the required synthetic intermediates often make them poor substrates in synthetic schemes designed around conventional organometallic cross-coupling. Here, strong benzodiimine-based acceptors, including 5,6-difluoro[2,1,3]benzothiadiazole, 5,6-dicyano[2,1,3]benzothiadiazole, 5,6-dicyanobenzo[d][1,2,3]triazole, 6,7-dicyanoquinoxaline, and 6,7-dinitroquinoxaline, are shown to undergo facile palladium-catalyzed C-H direct arylation with a variety of bromoarenes in moderate to high yields. The electrochemical characteristics of di-2-thienyl derivatives synthesized using this methodology are compared and suggest that, in an electron-transfer sense, 5,6-dicyano[2,1,3]benzothiadiazole is a comparably strong acceptor to benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole. The synthetic results suggest that high electron-withdrawing ability, which has traditionally limited reaction yields and structural variety in organic electronic materials, may be advantageous when employing C-H activated direct arylation in certain circumstances.

Replicating research in ecology and evolution: feasibility, incentives, and the cost-benefit conundrum.

We believe that replicating studies in ecology and evolution is extremely valuable, but replication within species and systems is troublingly rare, and even 'quasi-replications' in different systems are often insufficient. We make a case for supporting multiple types of replications and point out that the current incentive structure needs to change if ecologists and evolutionary biologist are to value scientific replication sufficiently.

Controllable direct arylation: fast route to symmetrical and unsymmetrical 4,7-diaryl-5,6-difluoro-2,1,3-benzothiadiazole derivatives for organic optoelectronic materials.

Arylation in the 4- and 7-positions of 2,1,3-benzothiadiazole (BT) and its monofluoro- (MFBT) and difluoro- (DFBT) derivatives by (hetero)aryl bromides using Pd-catalyzed C­H activation has been investigated. MFBT and DFBT can be diarylated in moderate to high yields (up to 96% for DFBT) by a variety of aryl bromides. DFBT can be sequentially arylated using two different aryl bromides to give differentially substituted DFBT derivatives. The moderate to high yields of doubly arylated MFBT and DFBT and the ability to obtain differentially substituted products can be applied to a variety of organic photonic and electronic materials.

Lacustrine sedimentation by powerful storm waves in Gale crater and its implications for a warming episode on Mars.

This investigation documents that the Rugged Terrain Unit, the Stimson formation, and the Greenheugh sandstone were deposited in a 1200 m-deep lake that formed after the emergence of Mt. Sharp in Gale crater, Mars, nearly 4 billion years ago. In fact, the Curiosity rover traversed on a surface that once was the bottom of this lake and systematically examined the strata that were deposited in its deepest waters on the crater floor to layers that formed along its shoreline on Mt. Sharp. This provided a rare opportunity to document the evolution of one aqueous episode from its inception to its desiccation and to determine the warming mechanism that caused it. Deep water lacustrine siltstones directly overlie conglomerates that were deposited by mega floods on the crater floor. This indicates that the inception phase of the lake was sudden and took place when flood waters poured into the crater. The lake expanded quickly and its shoreline moved up the slope of Mt. Sharp during the lake-level rise phase and deposited a layer of sandstone with large cross beds under the influence of powerful storm waves. The lake-level highstand phase was dominated by strong bottom currents that transported sediments downhill and deposited one of the most distinctive sedimentological features in Gale crater: a layer of sandstone with a 3 km-long field of meter-high subaqueous antidunes (the Washboard) on Mt. Sharp. Bottom current continued downhill and deposited sandstone and siltstone on the foothills of Mt. Sharp and on the crater floor, respectively. The lake-level fall phase caused major erosion of lacustrine strata that resulted in their patchy distribution on Mt. Sharp. Eroded sediments were then transported to deep waters by gravity flows and were re-deposited as conglomerate and sandstone in subaqueous channels and in debris flow fans. The desiccation phase took place in calm waters of the lake. The aqueous episode we investigated was vigorous but short-lived. Its characteristics as determined by our sedimentological study matches those predicted by an asteroid impact. This suggests that the heat generated by an impact transformed Mars into a warm, wet, and turbulent planet. It resulted in planet-wide torrential rain, giant floods on land, powerful storms in the atmosphere, and strong waves in lakes. The absence of age dates prevents the determination of how long the lake existed. Speculative rates of lake-level change suggest that the lake could have lasted for a period ranging from 16 to 240 Ky.

Tailoring On-Surface Molecular Reactions and Assembly through Hydrogen-Modified Synthesis: From Triarylamine Monomer to 2D Covalent Organic Framework.

Relative to conventional wet-chemical synthesis techniques, on-surface synthesis of organic networks in ultrahigh vacuum has few control parameters. The molecular deposition rate and substrate temperature are typically the only synthesis variables to be adjusted dynamically. Here we demonstrate that reducing conditions in the vacuum environment can be created and controlled without dedicated sources─relying only on backfilled hydrogen gas and ion gauge filaments─and can dramatically influence the Ullmann-like on-surface reaction used for synthesizing two-dimensional covalent organic frameworks (2D COFs). Using tribromo dimethylmethylene-bridged triphenylamine ((Br3)DTPA) as monomer precursors, we find that atomic hydrogen (H•) blocks aryl-aryl bond formation to such an extent that we suspect this reaction may be a factor in limiting the ultimate size of 2D COFs created through on-surface synthesis. Conversely, we show that control of the relative monomer and hydrogen fluxes can be used to produce large self-assembled islands of monomers, dimers, or macrocycle hexamers, which are of interest in their own right. On-surface synthesis of oligomers, from a single precursor, circumvents potential challenges with their protracted wet-chemical synthesis and with multiple deposition sources. Using scanning tunneling microscopy and spectroscopy (STM/STS), we show that changes in the electronic states through this oligomer sequence provide an insightful view of the 2D COF (synthesized in the absence of atomic hydrogen) as the end point in an evolution of electronic structures from the monomer.

Predicting reliability through structured expert elicitation with the repliCATS (Collaborative Assessments for Trustworthy Science) process.

As replications of individual studies are resource intensive, techniques for predicting the replicability are required. We introduce the repliCATS (Collaborative Assessments for Trustworthy Science) process, a new method for eliciting expert predictions about the replicability of research. This process is a structured expert elicitation approach based on a modified Delphi technique applied to the evaluation of research claims in social and behavioural sciences. The utility of processes to predict replicability is their capacity to test scientific claims without the costs of full replication. Experimental data supports the validity of this process, with a validation study producing a classification accuracy of 84% and an Area Under the Curve of 0.94, meeting or exceeding the accuracy of other techniques used to predict replicability. The repliCATS process provides other benefits. It is highly scalable, able to be deployed for both rapid assessment of small numbers of claims, and assessment of high volumes of claims over an extended period through an online elicitation platform, having been used to assess 3000 research claims over an 18 month period. It is available to be implemented in a range of ways and we describe one such implementation. An important advantage of the repliCATS process is that it collects qualitative data that has the potential to provide insight in understanding the limits of generalizability of scientific claims. The primary limitation of the repliCATS process is its reliance on human-derived predictions with consequent costs in terms of participant fatigue although careful design can minimise these costs. The repliCATS process has potential applications in alternative peer review and in the allocation of effort for replication studies.

Challenges and Experiences of Managed Aquifer Recharge in the Mexico City Metropolitan Area.

The Mexico City Metropolitan Area (MCMA) is a significant and important urban center in North America, covering an area of approximately 9500 km2 with a population of almost 23 million, yet the water supply remains unsustainable. The total water demand in the MCMA is 84 m3 /s and is provided by groundwater (63% or 53 m3 /s), imported water (27% or 23 m3 /s) and recycled water (10% or 8 m3 /s). The natural recharge of the MCMA aquifer is approximately 23 m3 /s, indicating an overexploitation of groundwater resources of approximately 25 m3 /s (800 Mm3 annually), a reasonable future goal for recharge in the MCMA. Hydrologic analysis indicates two main opportunities currently to increase water supply in the MCMA: indirect water reuse with recycled water and managed aquifer recharge (MAR) with storm water. An inventory of MAR project case studies in the MCMA summarizes methods for recharge, water sources, geographical distribution, and the main results obtained in each project for the last 80 years. The inventory consists of 21 MCMA area MAR case studies including (1) conceptual, (2) design level, and (3) pilot- to full-scale facilities, only some of which have operated for relatively short periods of time, with one remaining MAR project currently operational. The review found that beyond the technical and economic issues that MAR project design normally address, the existing regulatory framework and the continuous change in water district chairs in charge of the operation and supply of water are significant barriers to increasing MAR in the MCMA.

Applied Geophysics for Managed Aquifer Recharge.

Increasing water stress and decreasing supplies caused by growth and climate variability have expanded demand for managed aquifer recharge (MAR) projects to provide water supply resilience. Some of the most important factors in determining the performance of a MAR project include site selection, subsurface hydrogeologic characteristics and associated properties of the storage zone. Costs for invasive subsurface investigations to address these factors have slowly increased over the past two decades, with drilling costs increasing dramatically by as much as 30% or more since COVID-19 hit, a result of supply chain issues, steel prices, and manpower challenges. This paper provides a high-level review of major geophysical methods that have become more mainstream over the past decade or two to supplement invasive subsurface investigations and are very cost effective when compared to drilling boreholes and installing wells, which provide only point data. The more commonly used surface geophysical methods include ground-based and airborne time-domain electromagnetic methods (TEM), electrical resistivity, and seismic reflection. Airborne TEM methods (AEM) collect data very quickly, avoiding ground-based access constraints, and land-based methods are especially efficient using towed arrays. Electrical resistivity measurements provide resolution comparable to TEM but require more time than towed methods. Seismic reflection surveys are more expensive than other methods but typically have a much greater depth of penetration and can provide high resolution information on aquifer geometry, geology, and faults. Borehole geophysics is one of the more common methods used in MAR, providing near hole formation data and ground truths surface geophysics.