Oxycodone-induced dopaminergic and respiratory effects are modulated by deep brain stimulation

Introduction: Opioids are the leading cause of overdose death in the United States, accounting for almost 70,000 deaths in 2020. Deep brain stimulation (DBS) is a promising new treatment for substance use disorders. Here, we hypothesized that VTA DBS would modulate both the dopaminergic and respiratory effect of oxycodone. Methods: Multiple-cyclic square wave voltammetry (M-CSWV) was used to investigate how deep brain stimulation (130 Hz, 0.2 ms, and 0.2 mA) of the rodent ventral segmental area (VTA), which contains abundant dopaminergic neurons, modulates the acute effects of oxycodone administration (2.5 mg/kg, i.v.) on nucleus accumbens core (NAcc) tonic extracellular dopamine levels and respiratory rate in urethane-anesthetized rats (1.5 g/kg, i.p.). Results: I.V. administration of oxycodone resulted in an increase in NAcc tonic dopamine levels (296.9 ± 37.0 nM) compared to baseline (150.7 ± 15.5 nM) and saline administration (152.0 ± 16.1 nM) (296.9 ± 37.0 vs. 150.7 ± 15.5 vs. 152.0 ± 16.1, respectively, p = 0.022, n = 5). This robust oxycodone-induced increase in NAcc dopamine concentration was associated with a sharp reduction in respiratory rate (111.7 ± 2.6 min-1 vs. 67.9 ± 8.3 min-1; pre- vs. post-oxycodone; p < 0.001). Continuous DBS targeted at the VTA (n = 5) reduced baseline dopamine levels, attenuated the oxycodone-induced increase in dopamine levels to (+39.0% vs. +95%), and respiratory depression (121.5 ± 6.7 min-1 vs. 105.2 ± 4.1 min-1; pre- vs. post-oxycodone; p = 0.072). Discussion: Here we demonstrated VTA DBS alleviates oxycodone-induced increases in NAcc dopamine levels and reverses respiratory suppression. These results support the possibility of using neuromodulation technology for treatment of drug addiction

Nonlinear truss models for strain‐based seismic evaluation of planar RC walls

This paper introduces a new approach for the seismic performance evaluation of planar RC walls. Compared to existing assessment guidelines, such as those in ASCE/SEI 41-17, where performance limits are described by plastic rotation or lateral drift, the proposed method uses local (strain) quantities, obtained from computational models. The analyses rely on a user-friendly implementation of the nonlinear truss model for RC structures, which eliminates the need to manually create a line-element representation of a wall and includes a material law for steel accounting for buckling and rupture of reinforcement. The capability of the models to capture common failure patterns for planar walls is validated for a set of six previously tested wall components which experienced a variety of damage modes (bar rupture, boundary element failure, diagonal compression and tension failures). The analytical models accurately predict the lateral strength, deformation capacity and failure modes observed in the tests. A set of acceptance criteria, based on the analytically obtained concrete and steel strains, is then established for the immediate occupancy, life safety and collapse prevention levels, consistent with different levels and types of damage. An initial calibration of the limit values associated with these criteria is proposed and verified using the analytical results for the six walls considered. The results of the proposed assessment methodology applied to the six walls are compared to those obtained using the nonlinear procedures in ASCE/SEI 41-17. The results indicate that ASCE/SEI 41-17 may not accurately describe the deformability of walls exhibiting mixed flexure-shear inelastic deformations.The research presented in this paper is supported by the National Institute of Standards and Technology (NIST) under award No. 70NANB19H060. Any opinions and findings presented in this paper are those of the authors alone, and do not necessarily reflect the opinions of the sponsor.Peer ReviewedPostprint (published version

Effect of different types of statins on kidney function decline and proteinuria: a network meta-analysis

Previous studies showed that statins reduce the progression of kidney function decline and proteinuria, but whether specific types of statins are more beneficial than others remains unclear. We performed a network meta-analysis of randomized controlled trials (RCT) to investigate which statin most effectively reduces kidney function decline and proteinuria. We searched MEDLINE, Embase, Web of Science, and the Cochrane database until July 13, 2018, and included 43 RCTs (>110,000 patients). We performed a pairwise random-effects meta-analysis and a network meta-analysis according to a frequentist approach. We assessed network inconsistency, publication bias, and estimated for each statin the probability of being the best treatment. Considerable heterogeneity was present among the included studies. In pairwise meta-analyses, 1-year use of statins versus control reduced kidney function decline by 0.61(95%-CI: 0.27; 0.95) mL/min/1.73 m(2) and proteinuria with a standardized mean difference of -0.58 (95%-CI:-0.88; -0.29). The network meta-analysis for the separate endpoints showed broad confidence intervals due to the small number available RCTs for each individual comparison. In conclusion, 1-year statin use versus control attenuated the progression of kidney function decline and proteinuria. Due to the imprecision of individual comparisons, results were inconclusive as to which statin performs best with regard to renal outcome.Diabetes mellitus: pathophysiological changes and therap

Achievement of target gain larger than unity in an inertial fusion experiment

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result