Results of two Phase 1, Randomized, Double-blind, Placebo-controlled, Studies (Ascending Single-dose and Multiple-dose Studies) to Determine the Safety, Tolerability, and Pharmacokinetics of Orally Administered LX9211 in Healthy Participants.

PURPOSE: For neuropathic pain, current therapies do not provide relief for most patients; less than half achieve a 50% pain reduction. Current analgesics have adverse effects. We present 2 Phase I studies of LX9211, a new small-molecule AP2-associated kinase 1 inhibitor with preclinical effectiveness in pain relief. METHODS: Both randomized, placebo-controlled studies' primary objectives evaluated the tolerability and pharmacokinetic properties of oral LX9211. In the single-ascending dose (SAD) study, single, oral, liquid doses of 5, 10, 15, 20, 30, 40, 80, 120, 160, 200, and 300 mg of LX9211 or placebo were administered in the fasted state and 40 mg in a fed group. In the multiple-ascending dose (MAD) study, a loading dose was administered on day 1 and maintenance doses were administered daily on days 2 to 14. The treatment groups were designated as: 25/2.5, 50/5.0, 100/10, 150/15, and 200/20 mg. The secondary objectives included ECG evaluation. FINDINGS: The SAD study enrolled 96 participants 19 to 61 years of age (86.5% male) in 12 cohorts (2:6 placebo:LX9211), and the MAD study enrolled 50 participants 20 to 63 years of age (78% male) in 5 cohorts (2:8 placebo:LX9211). Both studies had a good LX9211 safety profile. No deaths or serious adverse events occurred. All treatment-emergent adverse events (TEAEs) were mild, except for moderate nausea and vomiting reported in 1 participant in the SAD 300-mg cohort. All TEAEs were considered recovered or resolved, except for blurred vision (n = 1 in the SAD 300-mg group), which was ongoing at the last visit. One participant in the MAD study (50/5 mg group) discontinued participation in the study early because of TEAEs (angioedema, dermatitis allergic, and urticaria). Headache, dizziness, constipation, and nausea were the most common TEAEs. In the SAD study, 4 participants in the 200-mg cohort developed headache approximately 24 hours after dosing, lasting 24 to 48 hours. Only 1 required treatment (acetaminophen). No notable ECG changes from baseline were found in either study. After both single- and multiple-dose administration, plasma exposure of LX9211 was approximately dose proportional. Steady-state LX9211 plasma concentrations were rapidly attained and maintained by a dosing regimen of a loading dose, followed by daily maintenance doses (1/10 the loading dose). No accumulation was as seen after multiple dosing. IMPLICATIONS: These studies found that LX9211 was safe and well tolerated in healthy participants. These findings suggest it is appropriate to take LX9211 forward into Phase II studies of patients with diabetic peripheral neuropathic pain and postherpetic neuralgia. LX9211 has received fast track designation by the US Food and Drug Administration.

Evaluating the holistic costs and benefits of corn production systems in Minnesota, US.

Global agriculture aims to minimize its impacts on environment and human health while maintaining its productivity. This requires a comprehensive understanding of its benefits and costs to ecosystems and society. Here, we apply a new evaluation framework developed by the Economics of Ecosystems and Biodiversity for Agriculture and Food (TEEBAgriFood) to assess key benefits and costs on the production side of genetically modified (GM) and organic corn systems in Minnesota, USA. The market value of GM corn is $4.5 billion, and only $31.8 million for organic corn using production data and market prices of 2017. GM corn generates revenue of $1488 per hectare (at $121 per MT), which is significantly lower than the organic corn at $2793 per hectare (at $294 per MT). Using a novel three-stage wellbeing valuation, analysis of the associations between corn production intensity and subjective measures of general health and wellbeing indicates that the total non-financial health cost associated with GM corn is $427.50 per hectare or $1.3 billion annually. We also find that the total annual environmental cost associated with GM corn production is $179 per hectare or $557.65 million within Minnesota. The use of the evaluation framework can help to improve decision making at farm and policy level to develop sustainable agriculture in order to minimize environmental and health related costs to society and economy.

Incorporating Routine Magnetic Resonance Imaging-based Planning for the Delivery of High-dose-rate Brachytherapy for Prostate Cancer: An Evaluation of Clinical Feasibility and Dosimetric Outcomes.

Introduction To evaluate the implementation and dosimetric outcomes of magnetic resonance imaging (MRI) planning for improved target and normal tissue definition for the treatment of prostate cancer with high-dose-rate brachytherapy (HDRBT). Methods From August 2015 to October 2017, 137 unique patients with newly diagnosed localized prostate cancer underwent a total of 174 outpatient brachytherapy procedures using MRI-based treatment planning. Patients receiving brachytherapy as monotherapy underwent two separate procedures while those receiving brachytherapy as a boost after external beam radiation therapy underwent a single procedure. The target volume was defined as the prostate +/- seminal vesicles as clinically appropriate without any additional margin. Pre-treatment dose-volume histogram (DVH) goals to the target were: D90≥95%, V90≥95%, V100≥90%, V150≤30%, V200≤15%. DVH goals to organs-at-risk (OARs): urethra D.01cc ≤115%, bladder D1cc ≤75%, rectum D1cc ≤75%, neurovascular bundle D0.1cc ≤100%, penile bulb D1cc ≤100%. Procedure times were recorded at each step of the procedure, from catheter insertion to removal. Results The median target volume was 45.9 cc, the median volume receiving the prescription dose was 53.0 cc, and the median selectivity index was 0.9. The median values for target dosimetry were as follows: D90=99.9%, V90=95.7%, V100=90.1%, V150=28.1%, V200=10.5%. The median values for OAR dosimetry were: urethra D.01cc=114.3%, bladder D1cc=68.3%, rectum D1cc=51.8%, left neurovascular bundle D0.1cc=86.8%, right neurovascular bundle D0.1cc=88.5%, penile bulb D1cc=31.7%. The median time from catheter insertion to end of HDRBT delivery was four hours 14 minutes (range 2:56-9:08); total treatment package time was five hours 32 minutes (range 3:31-9:45). Conclusion Routine MRI-based treatment planning is feasible for the delivery of HDRBT for prostate cancer. We met stringent dosimetric criteria despite more objective target and normal tissue definition with MRI imaging. Treatment package time remains reasonable. We have adopted MRI as our standard imaging modality for HDRBT for prostate cancer.

Genetically tunable M13 phage films utilizing evaporating droplets.

This effort utilizes a genetically tunable system of bacteriophage to evaluate the effect of charge, temperature and particle concentration on biomaterial synthesis utilizing the coffee ring (CR) effect. There was a 1.6-3 fold suppression of the CR at higher temperatures while maintaining self-assembled structures of thin films. This suppression was observed in phage with charged and uncharged surface chemistry, which formed ordered and disordered assemblies respectively, indicating CR suppression is not dependent on short-range ordering or surface chemistry. Analysis of the drying process suggests weakened capillary flow at elevated temperatures caused CR suppression and could be further enhanced for controlled assembly for advanced biomaterials.

Confined space ventilation by shipyard welders: observed use and effectiveness.

Shipbuilding involves intensive welding activities within enclosed and confined spaces, and although ventilation is commonly used in the industry, its use and effectiveness has not been adequately documented. Workers engaged in welding in enclosed or confined spaces in two shipyards were observed for their use of ventilation and monitored for their exposure to particulate matter. The type of ventilation in use, its placement and face velocity, the movement of air within the space, and other ventilation-related parameters were recorded, along with task characteristics such as the type of welding, the welder's position, and the configuration of the space. Mechanical ventilation was present in about two-thirds of the 65 welding scenarios observed, with exhaust ventilation used predominantly in one shipyard and supply blowers predominantly in the other. Welders were observed working in apparent dead-spaces within the room in 53% of the cases, even where ventilation was in use. Respiratory protection was common in the two shipyards, observed in use in 77 and 100% of the cases. Welding method, the proximity of the welder's head to the fume, and air mixing were found to be significantly associated with the welder's exposure, while other characteristics of dilution ventilation did not produce appreciable differences in exposure level. These parameters associated with exposure reduction can be assessed subjectively and are thus good candidates for training on effective ventilation use during hot work in confined spaces. Ventilation used in confined space welding is often inadequate for controlling exposure to welding fume.

Conserved toxic responses across divergent phylogenetic lineages: a meta-analysis of the neurotoxic effects of RDX among multiple species using toxicogenomics.

At military training sites, a variety of pollutants such as hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), may contaminate the area originating from used munitions. Studies investigating the mechanism of toxicity of RDX have shown that it affects the central nervous system causing seizures in humans and animals. Environmental pollutants such as RDX have the potential to affect many different species, therefore it is important to establish how phylogenetically distant species may respond to these types of emerging pollutants. In this paper, we have used a transcriptional network approach to compare and contrast the neurotoxic effects of RDX among five phylogenetically disparate species: rat (Sprague-Dawley), Northern bobwhite quail (Colinus virginianus), fathead minnow (Pimephales promelas), earthworm (Eisenia fetida), and coral (Acropora formosa). Pathway enrichment analysis indicated a conservation of RDX impacts on pathways related to neuronal function in rat, Northern bobwhite quail, fathead minnows and earthworm, but not in coral. As evolutionary distance increased common responses decreased with impacts on energy and metabolism dominating effects in coral. A neurotransmission related transcriptional network based on whole rat brain responses to RDX exposure was used to identify functionally related modules of genes, components of which were conserved across species depending upon evolutionary distance. Overall, the meta-analysis using genomic data of the effects of RDX on several species suggested a common and conserved mode of action of the chemical throughout phylogenetically remote organisms.