Routes to Advanced Intermediates in the Synthesis of Tetracarbocyclic Sesquiterpenoids Daphnenoid A and Artatrovirenols A and B.

A short route from dihydrocarvone is described, which led to the tetracarbocyclic core common to artatrovirenol A and B and daphnenoid A. A variant of this route afforded guaia-4,6-dien-3-one (from Enterospermum madagascarensis) and its epimer. From 2-(2-oxoethyl)furan, a 15-step sequence then delivered the complete carbon skeleton and all functionality necessary for daphnenoid A. Key steps in the route include diastereoselective intramolecular oxidopyrylium cycloaddition, oxa-bridge cleavage under "push-pull" conditions, and intramolecular Diels-Alder cycloaddition.

Selective P450BM3 Hydroxylation of Cyclobutylamine and Bicyclo[1.1.1]pentylamine Derivatives: Underpinning Synthetic Chemistry for Drug Discovery.

Achieving single-step syntheses of a set of related compounds divergently and selectively from a common starting material affords substantial efficiency gains when compared with preparing those same compounds by multiple individual syntheses. In order for this approach to be realized, complementary reagent systems must be available; here, a panel of engineered P450BM3 enzymes is shown to fulfill this remit in the selective C-H hydroxylation of cyclobutylamine derivatives at chemically unactivated sites. The oxidations can proceed with high regioselectivity and stereoselectivity, producing valuable bifunctional intermediates for synthesis and applications in fragment-based drug discovery. The process also applies to bicyclo[1.1.1]pentyl (BCP) amine derivatives to achieve the first direct enantioselective functionalization of the bridging methylenes and open a short and efficient route to chiral BCP bioisosteres for medicinal chemistry. The combination of substrate, enzyme, and reaction engineering provides a powerful general platform for small-molecule elaboration and diversification.

Two Total Syntheses of Trigoxyphins K and L.

Two total syntheses are presented for trigoxyphins K and L, tricyclic terpenoids from Trigonostemon xyphophylloides. The first proceeds via electrophlic cyclization in A/C-ring substrates to close the B ring at C4-C5 and then 1O2-mediated hydroxybutenolide formation to trigoxyphin L, with Luche reduction leading to trigoxyphin K. The second route develops from tetralone ring expansion to a B/C-ring intermediate that, by one-step O-demethylation-lactonization-isomerization, affords trigoxyphin K and then trigoxyphin L following enolate oxygenation.

Characterization of non-cardiac arrest PulsePoint activations in public and private settings.

BACKGROUND: Geospatial smartphone application alert systems are used in some communities to crowdsource community response for out-of-hospital cardiac arrest (OHCA). Although the clinical focus of this strategy is OHCA, dispatch identification of OHCA is imperfect so that activation may occur for the non-arrest patient. The frequency and clinical profile of such non-arrest patients has not been well-investigated. METHODS: We undertook a prospective 3-year cohort investigation of patients for whom a smartphone geospatial application was activated for suspected OHCA in four United States communities (total population ~1 million). The current investigation evaluates those patients with an activation for suspected OHCA who did not experience cardiac arrest. The volunteer response cohort included off-duty, volunteer public safety personnel (verified responders) notified regardless of location (public or private) and laypersons notified to public locations. The study linked the smartphone application information with the EMS records to report the frequency, condition type, and EMS treatment for these non-arrest patients. RESULTS: Of 1779 calls where volunteers were activated, 756 had suffered OHCA, resulting in 1023 non-arrest patients for study evaluation. The most common EMS assessments were syncope (15.9%, n=163), altered mental status (15.5%, n=159), seizure (14.3%, n=146), overdose (13.0%, n=133), and choking (10.5%, n=107). The assessment distribution was similar for private and public locations. Overall, the most common EMS interventions included placement of an intravenous line (43.1%, n=441), 12-Lead ECG(27.9%, n=285), naloxone treatment (9.8%, n=100), airway or ventilation assistance (8.7%, n=89), and oxygen administration (6.6%, n=68). CONCLUSIONS: More than half of patients activated for suspected OHCA had conditions other than cardiac arrest. A subset of these conditions may benefit from earlier care that could be provided by both layperson and public safety volunteers if they were appropriately trained and equipped.

An Enantiospecific Synthesis of 5-epi-α-Bulnesene.

As a result of its unique fragrance and wider role in traditional medicine, agarwood produced in Aquilaria spp. and certain other trees has been harvested to near extinction as a natural phenomenon. Artificially induced agarwood production in Aquilaria plantations has sated some of the demand although the product quality is variable. Synthetic chemistry may have a role to play in providing sustainable routes to many of the fragrant components identified in agarwood and its smoke when burnt as incense. In this work, we report efforts towards a total synthesis of the guaiane sesquiterpene α-bulnesene, which is found, along with its more fragrant oxidised derivatives, in agarwood. Following the ring-expansion of (R)-carvone using reported procedures, α-butenylation gave a substrate for samarium diiodide mediated reductive cyclisation, the two butenyl epimers of the substrate each leading to a single bicyclic alcohol (24 and 25). Overall homoconjugate hydride reduction of one of these alcohols was achieved by Lewis acid-mediated ionisation and then hydride transfer from triethylsilane to complete an overall seven-step synthesis of 5-epi-α-bulnesene. This new synthesis paves the way for short routes to both α-bulnesene enantiomers and a study of their aerial and enzymatic oxidation products.

Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration.

ETS2 repressor factor (ERF) insufficiency causes craniosynostosis (CRS4) in humans and mice. ERF is an ETS domain transcriptional repressor regulated by Erk1/2 phosphorylation via nucleo-cytoplasmic shuttling. Here, we analyze the onset and development of the craniosynostosis phenotype in an Erf-insufficient mouse model and evaluate the potential of the residual Erf activity augmented by pharmacological compounds to ameliorate the disease. Erf insufficiency appears to cause an initially compromised frontal bone formation and subsequent multisuture synostosis, reflecting distinct roles of Erf on the cells that give rise to skull and facial bones. We treated animals with Mek1/2 and nuclear export inhibitors, U0126 and KPT-330, respectively, to increase Erf activity by two independent pathways. We implemented both a low dosage locally over the calvaria and a systemic drug administration scheme to evaluate the possible indirect effects from other systems and minimize toxicity. The treatment of mice with either the inhibitors or the administration scheme alleviated the synostosis phenotype with minimal adverse effects. Our data suggest that the ERF level is an important regulator of cranial bone development and that pharmacological modulation of its activity may represent a valid intervention approach both in CRS4 and in other syndromic forms of craniosynostosis mediated by the FGFR-RAS-ERK-ERF pathway.

Australian and New Zealand consensus guideline for paediatric newly diagnosed immune thrombocytopaenia endorsed by Australian New Zealand Children's Haematology and Oncology Group.

In children, the majority of cases are self-limiting and thus many paediatric patients can be managed conservatively with minimal complications. This varies considerably compared to adult newly diagnosed immune thrombocytopaenia (NDITP) where, in most cases, thrombocytopaenia persists with higher risk of moderate to severe bleeding complications. In the past decade, local and international guidelines have emerged to support approaches to the investigation and management of NDITP, with a focus primarily on adult immune thrombocytopaenia (ITP). International consensus guidelines on paediatric NDITP have been developed, however gaps remain, and approaches vary between North American, Asia, Europe and the UK. There are no current Australian or New Zealand paediatric ITP guidelines readily available, rather differing guidelines for each state, territory or island. These inconsistencies cause uncertainty for patients, families and physicians managing cases. Subsequently, physicians, including paediatric haematologists and general paediatricians, have come together to provide a consensus approach guideline specific to paediatric NDITP for Australian or New Zealand. Persistent or chronic paediatric ITP remains a complex and separate entity and are not discussed here.

Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR Trial): Protocol for a Randomized Controlled Trial.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides support for the pulmonary or cardiovascular function of children in whom the predicted mortality risk remains very high. The inevitable host inflammatory response and activation of the coagulation cascade due to the extracorporeal circuit contribute to additional morbidity and mortality in these patients. Mixing nitric oxide (NO) into the sweep gas of ECMO circuits may reduce the inflammatory and coagulation cascade activation during ECMO support. OBJECTIVE: The purpose of this study is to test the feasibility and safety of mixing NO into the sweep gas of ECMO systems and assess its effect on inflammation and coagulation system activation through a pilot randomized controlled trial. METHODS: The Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR) trial is an open-label, parallel-group, pilot randomized controlled trial to be conducted at a single center. Fifty patients who require ECMO support will be randomly assigned to receive either NO mixed into the sweep gas of the ECMO system at 20 ppm for the duration of ECMO or standard care (no NO) in a 1:1 ratio, with stratification by support type (veno-venous vs veno-arterial ECMO). RESULTS: Outcome measures will focus on feasibility (recruitment rate and consent rate, and successful inflammatory marker measurements), the safety of the intervention (oxygenation and carbon dioxide control within defined parameters and methemoglobin levels), and proxy markers of efficacy (assessment of cytokines, chemokines, and coagulation factors to assess the impact of NO on host inflammation and coagulation cascade activation, clotting of ECMO components, including computer tomography scanning of oxygenators for clot assessments), bleeding complications, as well as total blood product use. Survival without ECMO and the length of stay in the pediatric intensive care unit (PICU) are clinically relevant efficacy outcomes. Long-term outcomes include neurodevelopmental assessments (Ages and Stages Questionnaire, Strength and Difficulties Questionnaire, and others) and quality of life (Pediatric Quality of Life Inventory and others) measured at 6 and 12 months post ECMO cannulation. Analyses will be conducted on an intention-to-treat basis. CONCLUSIONS: The NECTAR study investigates the safety and feasibility of NO as a drug intervention during extracorporeal life support and explores its efficacy. The study will investigate whether morbidity and mortality in patients treated with ECMO can be improved with NO. The intervention targets adverse outcomes in patients who are supported by ECMO and who have high expected mortality and morbidity. The study will be one of the largest randomized controlled trials performed among pediatric patients supported by ECMO. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001518156; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376869. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/43760.

A low-dose rituximab regimen for first-line treatment of acquired haemophilia A.

A low-dose rituximab regimen for first-line treatment of acquired haemophilia A. INTRODUCTION: Acquired haemophilia A (AHA) is a rare disease caused by the development of autoantibodies against FVIII. Diagnosis involves confirmation of FVIII deficiency and the presence of an inhibitor via the Bethesda assay. Severe bleeding is often managed with bypassing agents such as recombinant factor VII. This is then followed by eradication of the inhibitor with immunosuppression which typically includes a corticosteroid backbone. AIM: Review the current management and outcomes of AHA in Queensland, Australia. Determine the incidence, demographics and clinical characteristics of AHA patients. METHODS: Retrospective case series of AHA diagnosed between May 2014 and August 2018. Data were derived from the Australian Bleeding Disorders Registry and state-wide pathology database. Data collection proforma was completed by the treating haematologist and reviewed/compiled centrally. RESULTS: 24 patients were identified (incidence 1 in 1.27 million). The median age was 76.5 years. Median follow-up was 20 months. Index bleed was atraumatic and skin/soft tissue in the majority of patients. Recombinant FVIIa was the most commonly used haemostatic therapy and effective in 85% of patients. Immunosuppression and steroid usage were uniform. Upfront second agent was used in 75% of patients and was most commonly rituximab. 87.5% of patients achieved a complete remission in a median time of 48 days. Low-dose rituximab was frequently used and equally as efficacious as standard dose. CONCLUSION: Immunosuppression with combination therapy, notably rituximab, appears to be non-inferior and has a favourable side effect profile.

ß-Hydroxybutyrate Oxidation in Exercise Is Impaired by Low-Carbohydrate and High-Fat Availability.

Purpose: In this study, we determined ketone oxidation rates in athletes under metabolic conditions of high and low carbohydrate (CHO) and fat availability. Methods: Six healthy male athletes completed 1 h of bicycle ergometer exercise at 75% maximal power (WMax) on three occasions. Prior to exercise, participants consumed 573 mg·kg bw-1 of a ketone ester (KE) containing a 13C label. To manipulate CHO availability, athletes undertook glycogen depleting exercise followed by isocaloric high-CHO or very-low-CHO diets. To manipulate fat availability, participants were given a continuous infusion of lipid during two visits. Using stable isotope methodology, ß-hydroxybutyrate (ßHB) oxidation rates were therefore investigated under the following metabolic conditions: (i) high CHO + normal fat (KE+CHO); (ii) high CHO + high fat KE+CHO+FAT); and (iii) low CHO + high fat (KE+FAT). Results: Pre-exercise intramuscular glycogen (IMGLY) was approximately halved in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both p < 0.05). Blood free fatty acids (FFA) and intramuscular long-chain acylcarnitines were significantly greater in the KE+FAT vs. other conditions and in the KE+CHO+FAT vs. KE+CHO conditions before exercise. Following ingestion of the 13C labeled KE, blood ßHB levels increased to ≈4.5 mM before exercise in all conditions. ßHB oxidation was modestly greater in the KE+CHO vs. KE+FAT conditions (mean diff. = 0.09 g·min-1, p = 0.03; d = 0.3), tended to be greater in the KE+CHO+FAT vs. KE+FAT conditions (mean diff. = 0.07 g·min-1; p = 0.1; d = 0.3) and were the same in the KE+CHO vs. KE+CHO+FAT conditions (p < 0.05; d < 0.1). A moderate positive correlation between pre-exercise IMGLY and ßHB oxidation rates during exercise was present (p = 0.04; r = 0.5). Post-exercise intramuscular ßHB abundance was markedly elevated in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both, p < 0.001; d = 2.3). Conclusion: ßHB oxidation rates during exercise are modestly impaired by low CHO availability, independent of circulating ßHB levels.

RP-18 TLC Chromatographic and Computational Study of Skin Permeability of Steroids.

The skin permeability of steroids, as investigated in this study, is important because some of these compounds are, or could, be used in preparations applied topically. Several models of skin permeability, involving thin layer chromatographic and calculated descriptors, were generated and validated using Kp reference values obtained in silico and then tested on a group of solutes whose experimental Kp values could be found (log Kpexp). The study established that the most applicable log Kp model is based on RP-18 thin layer chromatographic data (RM) and the calculated descriptors VM (molar volume) and PSA (polar surface area). Two less efficient, yet simple, equations based on PSA or VM combined with HD (H-donor count) can be used with caution for rapid, rough estimations of compounds' skin permeability prior to their chemical synthesis.

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines.

A one-flask, two-step procedure from 3-amino-2-methyl-5,6,7,7a-tetrahydro-1H-pyrrolizin-1-one affords the Streptomyces secondary metabolites legonmycins A and B - three operations overall from methyl N-Boc-prolinate. The key step proceeds in each case via N,O-diacylation, then selective oxidative hydrolysis of the intermediate bicyclic pyrrole and establishes a precedent for the synthesis of related C(7a)-hydroxylated pyrrolizidines.

Application of RP-18 TLC Retention Data to the Prediction of the Transdermal Absorption of Drugs.

Several chromatographic parameters (RM0 and S obtained from RP-18 TLC with methanol-pH 7.4 phosphate buffer mobile phases by extrapolation to zero concentration of methanol; Rf and RM obtained from RP-18 TLC with acetonitrile-pH 7.4 phosphate buffer 70:30 v/v as a mobile phase) and calculated molecular descriptors (molecular weight-MW; molar volume-VM; polar surface area-PSA; total count of nitrogen and oxygen atoms-(N+O); H-bond donor count-HD; H-bond acceptor count-HA; distribution coefficient-log D; total energy-ET; binding energy-Eb; hydration energy-Eh; energy of the highest occupied molecular orbital-EHOMO; energy of the lowest unoccupied orbital-ELUMO; electronic energy-Ee; surface area-Sa; octanol-water partition coefficient-log P; dipole moment-DM; refractivity-R, polarizability-α) and their combinations (Rf/PSA, RM/MW, RM/VM) were tested in order to generate useful models of solutes' skin permeability coefficient log Kp. It was established that neither RM0 nor S obtained in the conditions used in this study is a good predictor of the skin permeability coefficient. The chromatographic parameters Rf and Rf/PSA were also unsuitable for this purpose. A simple and potentially useful, purely computational model based on (N+O), log D and HD as independent variables and accounting for ca. 83% of total variability was obtained. The evaluation of parameters derived from RM (RM, RM/MW, RM/VM) as independent variables in log Kp models proved that RM/VM is the most suitable descriptor belonging to this group. In a search for a reliable log Kp model based on this descriptor two possibilities were considered: a relatively simple model based on 5 independent variables: (N+O), log D, RM/VM, ET and Eh and a more complex one, involving also Eb, MW and PSA.

Enzymatic Kinetic Resolution by Addition of Oxygen.

Kinetic resolution using biocatalysis has proven to be an excellent complementary technique to traditional asymmetric catalysis for the production of enantioenriched compounds. Resolution using oxidative enzymes produces valuable oxygenated structures for use in synthetic route development. This Minireview focuses on enzymes which catalyse the insertion of an oxygen atom into the substrate and, in so doing, can achieve oxidative kinetic resolution. The Baeyer-Villiger rearrangement, epoxidation, and hydroxylation are included, and biological advancements in enzyme development, and applications of these key enantioenriched intermediates in natural product synthesis are discussed.

Improving response to out-of-hospital cardiac arrest: The verified responder program pilot.

BACKGROUND: Survival following out-of-hospital cardiac arrest (OHCA) decreases as the interval from collapse to CPR and defibrillation increases. Innovative approaches are needed to reduce response intervals, especially for private locations. METHODS: We undertook the Verified Responder Program in 5 United States communities during 2018, whereby off-duty EMS professionals volunteered and were equipped with automated external defibrillators (AEDs). Volunteers were alerted using a geospatial smartphone application (PulsePoint) and could respond to nearby private and public suspected OHCA. The study evaluated the frequency of Verified Responder notification, response, scene arrival, and initial care prior to EMS arrival. OHCA surveillance used the CARES registry. RESULTS: Of the 651 OHCA events (475 private, 176 public), Verified Responders were notified in 7.4% (n = 49). Among the 475 in a private location, volunteers were alerted in 8% (n = 38), responded in 2.7% (n = 13), arrived on scene in 2.3% (n = 11), and provided initial care in 1.7% (n = 8). Among the 176 in a public location, volunteers were alerted in 6.3% (n = 11), responded in 2.3% (n = 4), arrived on-scene in 2.3% (n = 4), and provided initial care in 2.3% (n = 4). Over 96% surveyed had positive impression of the program and intended to continue participation. No responder reported any adverse event. CONCLUSIONS: In this initial US-based experience of a smartphone program for suspected OHCA in private and public locations, Verified Responders reported a positive experience, though were only involved in a small fraction of OHCA. Studies should determine how this type of program could be enhanced to involve more OHCA events.

Circulation Cooling in Continuous Skin Sonoporation at Constant Coupling Fluid Temperatures.

Exposure of the skin to low-frequency ultrasound in the Franz diffusion cell has been found to increase the permeability of the skin to molecular transport. In many cases, significant heating of the coupling fluid requires the use of duty cycles that extend the total experimental time. This is a methodological study in which the coupling fluid is circulated between a modified Franz diffusion cell and a heat exchanger to allow for the continuous application of low-frequency ultrasound while the coupling fluid temperature is held constant. Dermatomed porcine skin was exposed to continuous ultrasound at 20 kHz for 10 min at an intensity of 55 W/cm2 while the coupling fluid was maintained at one of three target temperatures (13°C, 33°C or 46°C). Foil pitting and passive cavitation detection revealed that inertial cavitation activity decreased with increasing coupling fluid target temperature. Transport measurements revealed an increase in mean donor calcein concentration with increasing coupling fluid temperature, though these were not statistically significant. Taken together these findings suggest that the weakened stratum corneum lipid structure at higher temperatures is more susceptible to the introduction of defects from the jetting of cavitation.

Secondary Products from Intramolecular Cycloadditions of Azidoalkyl Enol Ethers and Azidoalkyl Vinyl Bromides: 1-Azadienes, Their Reactions with Diphenylketene, and Radical Cyclizations To Form Bi- and Tricyclic Lactams.

Azidoalkyl enol ethers undergo intramolecular 1,3-dipolar cycloaddition to generate stable triazolines; in contrast, the cycloadducts formed by heating analogous azidoalkyl vinyl bromides are unstable with respect to elimination of N2 and HBr, affording 1-azadienes (2-alkenyl cyclic imines). These primary products may be isolated or treated directly with diphenylketene to produce bi- and tricyclic 3,4-dihydropyridin-2(1H)-ones; similar ring systems may also be produced from the azadienes by N-acylation and radical cyclization.

Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies.

BACKGROUND: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. METHODS: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. FINDINGS: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. INTERPRETATION: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. FUNDING: Bayer AG, Janssen Research and Development.