A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study

Background: Ferroquine (SSR97193) is a candidate anti-malarial currently undergoing clinical trials for malaria. To better understand its pharmacokinetic (PK) and pharmacodynamic (PD) parameters the compound was tested in the experimentally induced blood stage malaria infection model in volunteers. Methods: Male and non-pregnant female aged 18-50 years were screened for this phase II, controlled, single-centre clinical trial. Subjects were inoculated with ~1800 viable Plasmodium falciparum 3D7A-infected human erythrocytes, and treated with a single-dose of 800 mg ferroquine. Blood samples were taken at defined time-points to measure PK and PD parameters. The blood concentration of ferroquine and its active metabolite, SSR97213, were measured on dry blood spot samples by ultra-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Parasitaemia and emergence of gametocytes were monitored by quantitative PCR. Safety was determined by recording adverse events and monitoring clinical laboratory assessments during the course of the study. Results: Eight subjects were enrolled into the study, inoculated with infected erythrocytes and treated with 800 mg ferroquine. Ferroquine was rapidly absorbed with maximal exposure after 4-8 and 4-12 h exposure for SSR97213. Non-compartmental PK analysis resulted in estimates for half-lives of 10.9 and 23.8 days for ferroquine and SSR97213, respectively. Parasite clearance as reported by parasite reduction ratio was 162.9 (95 % CI 141-188) corresponding to a parasite clearance half-life of 6.5 h (95 % CI: 6.4-6.7 h). PK/PD modelling resulted in a predicted minimal parasiticidal concentration of 20 ng/mL, and the single dosing tested in this study was predicted to maintain an exposure above this threshold for 454 h (37.8 days). Although ferroquine was overall well tolerated, transient elevated transaminase levels were observed in three subjects. Paracetamol was the only concomitant treatment among the two out of these three subjects that may have played a role in the elevated transaminases levels. No clinically significant ECG abnormalities were observed. Conclusions: The parameters and PK/PD model derived from this study pave the way to the further rational development of ferroquine as an anti-malarial partner drug. The safety of ferroquine has to be further explored in controlled human trials. Trial registration anzctr.org.au (registration number: ACTRN12613001040752), registered 18/09/201

Spectral decomposition of internal gravity wave sea surface height in global models

Two global ocean models ranging in horizontal resolution from 1/12° to 1/48° are used to study the space and time scales of sea surface height (SSH) signals associated with internal gravity waves (IGWs). Frequency‐horizontal wavenumber SSH spectral densities are computed over seven regions of the world ocean from two simulations of the HYbrid Coordinate Ocean Model (HYCOM) and three simulations of the Massachusetts Institute of Technology general circulation model (MITgcm). High wavenumber, high‐frequency SSH variance follows the predicted IGW linear dispersion curves. The realism of high‐frequency motions (>0.87  cpd) in the models is tested through comparison of the frequency spectral density of dynamic height variance computed from the highest‐resolution runs of each model (1/25° HYCOM and 1/48° MITgcm) with dynamic height variance frequency spectral density computed from nine in situ profiling instruments. These high‐frequency motions are of particular interest because of their contributions to the small‐scale SSH variability that will be observed on a global scale in the upcoming Surface Water and Ocean Topography (SWOT) satellite altimetry mission. The variance at supertidal frequencies can be comparable to the tidal and low‐frequency variance for high wavenumbers (length scales smaller than ∼50 km), especially in the higher‐resolution simulations. In the highest‐resolution simulations, the high‐frequency variance can be greater than the low‐frequency variance at these scales.Key PointsTwo high‐resolution ocean models compare well against data in frequency spectral density of dynamic heightSea surface height frequency‐horizontal wavenumber spectral densities show high variance along internal gravity wave dispersion curvesTwo high‐resolution ocean models give different estimates of variance in high‐frequency, high wavenumber phenomenaPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/1/jgrc22465-sup-0002-2017JC013009-fs01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/2/jgrc22465-sup-0003-2017JC013009-fs02.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/3/jgrc22465_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/4/jgrc22465.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/5/jgrc22465-sup-0007-2017JC013009-fs06.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/6/jgrc22465-sup-0009-2017JC013009-fs08.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/7/jgrc22465-sup-0004-2017JC013009-fs03.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/8/jgrc22465-sup-0005-2017JC013009-fs04.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/9/jgrc22465-sup-0006-2017JC013009-fs05.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/10/jgrc22465-sup-0001-2017JC013009-s01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/11/jgrc22465-sup-0008-2017JC013009-fs07.pd

Reduced functional measure of cardiovascular reserve predicts admission to critical care unit following kidney transplantation

Background: There is currently no effective preoperative assessment for patients undergoing kidney transplantation that is able to identify those at high perioperative risk requiring admission to critical care unit (CCU). We sought to determine if functional measures of cardiovascular reserve, in particular the anaerobic threshold (VO2AT) could identify these patients. Methods: Adult patients were assessed within 4 weeks prior to kidney transplantation in a University hospital with a 37-bed CCU, between April 2010 and June 2012. Cardiopulmonary exercise testing (CPET), echocardiography and arterial applanation tonometry were performed. Results: There were 70 participants (age 41.7614.5 years, 60% male, 91.4% living donor kidney recipients, 23.4% were desensitized). 14 patients (20%) required escalation of care from the ward to CCU following transplantation. Reduced anaerobic threshold (VO2AT) was the most significant predictor, independently (OR = 0.43; 95% CI 0.27–0.68; p,0.001) and in the multivariate logistic regression analysis (adjusted OR = 0.26; 95% CI 0.12–0.59; p = 0.001). The area under the receiveroperating- characteristic curve was 0.93, based on a risk prediction model that incorporated VO2AT, body mass index and desensitization status. Neither echocardiographic nor measures of aortic compliance were significantly associated with CCU admission. Conclusions: To our knowledge, this is the first prospective observational study to demonstrate the usefulness of CPET as a preoperative risk stratification tool for patients undergoing kidney transplantation. The study suggests that VO2AT has the potential to predict perioperative morbidity in kidney transplant recipients

Effects of grid spacing on high-frequency precipitation variance in coupled high-resolution global ocean–atmosphere models

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Light, C., Arbic, B., Martin, P., Brodeau, L., Farrar, J., Griffies, S., Kirtman, B., Laurindo, L., Menemenlis, D., Molod, A., Nelson, A., Nyadjro, E., O’Rourke, A., Shriver, J., Siqueira, L., Small, R., & Strobach, E. Effects of grid spacing on high-frequency precipitation variance in coupled high-resolution global ocean–atmosphere models. Climate Dynamics, (2022): 1–27, https://doi.org/10.1007/s00382-022-06257-6.High-frequency precipitation variance is calculated in 12 different free-running (non-data-assimilative) coupled high resolution atmosphere–ocean model simulations, an assimilative coupled atmosphere–ocean weather forecast model, and an assimilative reanalysis. The results are compared with results from satellite estimates of precipitation and rain gauge observations. An analysis of irregular sub-daily fluctuations, which was applied by Covey et al. (Geophys Res Lett 45:12514–12522, 2018. https://doi.org/10.1029/2018GL078926) to satellite products and low-resolution climate models, is applied here to rain gauges and higher-resolution models. In contrast to lower-resolution climate simulations, which Covey et al. (2018) found to be lacking with respect to variance in irregular sub-daily fluctuations, the highest-resolution simulations examined here display an irregular sub-daily fluctuation variance that lies closer to that found in satellite products. Most of the simulations used here cannot be analyzed via the Covey et al. (2018) technique, because they do not output precipitation at sub-daily intervals. Thus the remainder of the paper focuses on frequency power spectral density of precipitation and on cumulative distribution functions over time scales (2–100 days) that are still relatively “high-frequency” in the context of climate modeling. Refined atmospheric or oceanic model grid spacing is generally found to increase high-frequency precipitation variance in simulations, approaching the values derived from observations. Mesoscale-eddy-rich ocean simulations significantly increase precipitation variance only when the atmosphere grid spacing is sufficiently fine (< 0.5°). Despite the improvements noted above, all of the simulations examined here suffer from the “drizzle effect”, in which precipitation is not temporally intermittent to the extent found in observations.Support for CXL’s effort on this project was provided by a Research Experiences for Undergraduates (REU) supplement for National Science Foundation (NSF) grant OCE-1851164 to BKA, which also provided partial support for PEM. In addition, BKA acknowledges NSF grant OCE-1351837, which provided partial support for AKO, Office of Naval Research grant N00014-19-1-2712 and NASA grants NNX17AH55G, which also provided partial support for ADN, and 80NSSC20K1135. JTF’s participation, and the SPURS-II buoy data, were funded by NASA grants 80NSSC18K1494 and NNX15AG20G

Exposure Assessment in the National Children’s Study: Introduction

The science of exposure assessment is relatively new and evolving rapidly with the advancement of sophisticated methods for specific measurements at the picogram per gram level or lower in a variety of environmental and biologic matrices. Without this measurement capability, environmental health studies rely on questionnaires or other indirect means as the primary method to assess individual exposures. Although we use indirect methods, they are seldom used as stand-alone tools. Analyses of environmental and biologic samples have allowed us to get more precise data on exposure pathways, from sources to concentrations, to routes, to exposure, to doses. They also often allow a better estimation of the absorbed dose and its relation to potential adverse health outcomes in individuals and in populations. Here, we make note of various environmental agents and how best to assess exposure to them in the National Children’s Study—a longitudinal epidemiologic study of children’s health. Criteria for the analytical method of choice are discussed with particular emphasis on the need for long-term quality control and quality assurance measures

SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

SUMMARY A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression

The Main Belt Comets and ice in the Solar System

We review the evidence for buried ice in the asteroid belt; specifically the questions around the so-called Main Belt Comets (MBCs). We summarise the evidence for water throughout the Solar System, and describe the various methods for detecting it, including remote sensing from ultraviolet to radio wavelengths. We review progress in the first decade of study of MBCs, including observations, modelling of ice survival, and discussion on their origins. We then look at which methods will likely be most effective for further progress, including the key challenge of direct detection of (escaping) water in these bodies

Computing pseudotriangulations via branched coverings

We describe an efficient algorithm to compute a pseudotriangulation of a finite planar family of pairwise disjoint convex bodies presented by its chirotope. The design of the algorithm relies on a deepening of the theory of visibility complexes and on the extension of that theory to the setting of branched coverings. The problem of computing a pseudotriangulation that contains a given set of bitangent line segments is also examined.Comment: 66 pages, 39 figure

PFKFB3-Mediated Glycolysis Rescues Myopathic Outcomes in the Ischemic Limb

Compromised muscle mitochondrial metabolism is a hallmark of peripheral arterial disease, especially in patients with the most severe clinical manifestation — critical limb ischemia (CLI). We asked whether inflexibility in metabolism is critical for the development of myopathy in ischemic limb muscles. Using Polg mtDNA mutator (D257A) mice, we reveal remarkable protection from hind limb ischemia (HLI) due to a unique and beneficial adaptive enhancement of glycolytic metabolism and elevated ischemic muscle PFKFB3. Similar to the relationship between mitochondria from CLI and claudicating patient muscles, BALB/c muscle mitochondria are uniquely dysfunctional after HLI onset as compared with the C57BL/6 (BL6) parental strain. AAV-mediated overexpression of PFKFB3 in BALB/c limb muscles improved muscle contractile function and limb blood flow following HLI. Enrichment analysis of RNA sequencing data on muscle from CLI patients revealed a unique deficit in the glucose metabolism Reactome. Muscles from these patients express lower PFKFB3 protein, and their muscle progenitor cells possess decreased glycolytic flux capacity in vitro. Here, we show supplementary glycolytic flux as sufficient to protect against ischemic myopathy in instances where reduced blood flow–related mitochondrial function is compromised preclinically. Additionally, our data reveal reduced glycolytic flux as a common characteristic of the failing CLI patient limb skeletal muscle