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Analysis of entire transparent rodent bodies after clearing could provide holistic biological information in health and disease, but reliable imaging and quantification of fluorescent protein signals deep inside the tissues has remained a challenge. Here, we developed vDISCO, a pressure-driven, nanobody-based whole-body immunolabeling technology to enhance the signal of fluorescent proteins by up to two orders of magnitude. This allowed us to image and quantify subcellular details through bones, skin and highly autofluorescent tissues of intact transparent mice. For the first time, we visualized whole-body neuronal projections in adult mice. We assessed CNS trauma effects in the whole body and found degeneration of peripheral nerve terminals in the torso. Furthermore, vDISCO revealed short vascular connections between skull marrow and brain meninges, which were filled with immune cells upon stroke. Thus, our new approach enables unbiased comprehensive studies of the interactions between the nervous system and the rest of the body.

Background Neurodegenerative diseases such as Alzheimer’s are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. Methods Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30–180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. Results Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. Conclusion Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans.

Satellite charging in Earth's magnetospheric plasma and radiation belts frequently causes operational anomalies. A recent study of a frequent Space Wire anomaly on GOES linked it to shallow internal charging by 100–300 keV electrons. Solar wind and magnetospheric conditions during a period spanning solar minimum (2017–2021) are analyzed to gain further insight into the anomalies. The anomalies are divided into two groups, with inter‐anomaly intervals shorter than 2 days (clustered) and longer (background). The clusters sometimes exhibit a clear 27‐day recurrence. The magnetic local time (MLT) distributions for background anomalies are statistically uniform, unlike those for clustered anomalies, which peak prior to local noon. The clustered anomaly distributions with respect to Kp are similar to those for surface charging, indicating enhanced plasma sheet access to geostationary orbit. The maximum 100–300 keV fluxes during injections are similar to published extreme fluxes. Through superposed epoch analysis and comparison with published lists of high‐speed streams, clustered anomalies are determined to occur during high‐speed streams with elevated solar wind speed, lower number density, and weakly negative interplanetary magnetic field Bz ${B}_{z}$. The MLT and Kp dependencies of the clustered anomalies may indicate charge accumulating in a thin dielectric with a time constant less than 1 day. The background anomalies, occurring uniformly in local time and varying slowly between solar rotation periods, may indicate a distinct charging location with a time constant greater than a solar rotation.

A survey of 27 to 45 MeV proton measurements from the HEO‐3 satellite during the years 1998 through 2005 has been taken to describe variability in the outer part of the inner radiation belt and slot region (L = 2 to 3). Rapid (∼1‐day) changes are described as injection or loss events, characterized respectively by Gaussian or exponential L dependencies. The radial extent of both event types is correlated to the minimum Dst of associated magnetic storms, while the injection magnitude is correlated to the flux of associated interplanetary solar proton events. Changes in the maximal L of observed trapped protons are consistent with trapping limits estimated from magnetic field line curvature. The inward extent and energy independence of the observed loss events are inconsistent with field line curvature induced scattering in a static magnetic field. However, time‐dependent geomagnetic cutoff suppression, observed during magnetic storms, may be the cause of significant losses. Drift resonance with electric field impulses caused by rapid magnetospheric compression is the likely cause of both solar proton injections and radial shifts of preexisting trapped protons.

Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recreational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus, Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs. A multi-tiered screening approach was utilized, and any study or case report of generally healthy individuals exposed to any SARM was included. Thirty-three studies were included in the review with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (N = 1). Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may improve early detection and prevention of DILI.

Background Epilepsy is the fourth-most common neurological disorder, affecting an estimated 50 million patients globally. Nearly 40% of patients have uncontrolled seizures yet incur 80% of the cost. Anti-epileptic drugs commonly result in resistance and reversion to uncontrolled drug-resistant epilepsy and are often associated with significant adverse effects. This has led to a trial-and-error system in which physicians spend months to years attempting to identify the optimal therapeutic approach. Objective To investigate the potential clinical utility from the context of optimal therapeutic prediction of characterizing cellular electrophysiology. It is well-established that genomic data alone can sometimes be predictive of effective therapeutic approach. Thus, to assess the predictive power of electrophysiological data, machine learning strategies are implemented to predict a subject’s genetically defined class in an in silico model using brief electrophysiological recordings obtained from simulated neuronal networks. Methods A dynamic network of isogenic neurons is modeled in silico for 1-s for 228 dynamically modeled patients falling into one of three categories: healthy, general sodium channel gain of function, or inhibitory sodium channel loss of function. Data from previous studies investigating the electrophysiological and cellular properties of neurons in vitro are used to define the parameters governing said models. Ninety-two electrophysiological features defining the nature and consistency of network connectivity, activity, waveform shape, and complexity are extracted for each patient network and t-tests are used for feature selection for the following machine learning algorithms: Neural Network, Support Vector Machine, Gaussian Naïve Bayes Classifier, Decision Tree, and Gradient Boosting Decision Tree. Finally, their performance in accurately predicting which genetic category the subjects fall under is assessed. Results Several machine learning algorithms excel in using electrophysiological data from isogenic neurons to accurately predict genetic class with a Gaussian Naïve Bayes Classifier predicting healthy, gain of function, and overall, with the best accuracy, area under the curve, and F1. The Gradient Boosting Decision Tree performs the best for loss of function models indicated by the same metrics. Conclusions It is possible for machine learning algorithms to use electrophysiological data to predict clinically valuable metrics such as optimal therapeutic approach, especially when combining several models.

Radiation levels in Earth's outer electron belt (L ≳ 2.5) vary by orders of magnitude on the time scales ranging from minutes to days. Multiple acceleration and loss processes operate across the belt and compete in defining its global variability. One such process is the drift orbit bifurcation effect. Caused by coupling of the drift and bounce motions, it breaks the second adiabatic invariant of radiation belt electrons producing their transport in radius and pitch angle. In this paper we investigate implications of drift orbit bifurcations to the global state and variability of the outer electron belt. For this purpose we use three‐dimensional test particle simulations of electron guiding center motion in a realistic magnetic field model. We show that even at most quiet solar wind conditions bifurcations affect a broad range of the belt penetrating inside the geosynchronous orbit. This has an important practical implication for the analysis of experimental particle data: since the third adiabatic invariant is undefined for bifurcating orbit, the electron phase space density cannot be expressed in terms of three adiabatic invariants. We show that long‐term transport of electrons due to drift orbit bifurcations is a complex combination of large ballistic jumps and small‐amplitude diffusion in the second invariant and radial location. To model long‐term transport, we derive an empirical map of the second invariant and radial jumps at bifurcations. The map can also be implemented by other radiation belt models, which cannot directly account for the physics of drift orbit bifurcations. Drift orbit bifurcations can produce electron losses through the magnetopause escape and through pitch angle scattering into the atmospheric loss cone. Most electrons, however, can stay quasi‐trapped in the bifurcation regions for very long time periods. The pitch angle and radial transport due to drift orbit bifurcations lead to their meandering back and forth across the region producing mixing and recirculation of particle populations with different initial conditions. We show that this recirculation can greatly amplify electron energization by radial diffusion. Compared to the diffusion alone, the combined action of radial diffusion and drift orbit bifurcations can double electron energization at each recirculation cycle. Our results suggest that drift orbit bifurcations can play an important role in the buildup of increased electron fluxes in the storm recovery phase. Key Points Drift orbit bifurcations affect a broad range of the belt Drift orbit bifurcations produce electron losses from the belt Drift orbit bifurcations amplify electron energization by radial diffusion

Loop diuretics and antibiotics are commonly co-prescribed across many clinical care settings. Loop diuretics may alter antibiotic pharmacokinetics (PK) via several potential drug interactions. A systematic review of the literature was performed to investigate the impact of loop diuretics on antibiotic PK. The primary outcome metric was the ratio of means (ROM) of antibiotic PK parameters such as area under the curve (AUC) and volume of distribution (Vd) on and off loop diuretics. Twelve crossover studies were amenable for metanalysis. Coadministration of diuretics was associated with a mean 17% increase in plasma antibiotic AUC (ROM 1.17, 95% CI 1.09–1.25, I2 = 0%) and a mean decrease in antibiotic Vd by 11% (ROM 0.89, 95% CI 0.81–0.97, I2 = 0%). However, the half-life was not significantly different (ROM 1.06, 95% CI 0.99–1.13, I2 = 26%). The remaining 13 observational and population PK studies were heterogeneous in design and population, as well as prone to bias. No large trends were collectively observed in these studies. There is currently not enough evidence to support antibiotic dosing changes based on the presence or absence of loop diuretics alone. Further studies designed and powered to detect the effect of loop diuretics on antibiotic PK are warranted in applicable patient populations.

Plerixafor is a CXCR4 antagonist approved in 2008 by the FDA for hematopoietic stem cell collection. Subsequently, plerixafor has shown promise as a potential pathogen‐agnostic immunomodulator in a variety of preclinical animal models. Additionally, investigator‐led studies demonstrated plerixafor prevents viral and bacterial infections in patients with WHIM syndrome, a rare immunodeficiency with aberrant CXCR4 signaling. Here, we investigated whether plerixafor could be repurposed to treat sepsis or severe wound infections, either alone or as an adjunct therapy. In a Pseudomonas aeruginosa lipopolysaccharide (LPS)‐induced zebrafish sepsis model, plerixafor reduced sepsis mortality and morbidity assessed by tail edema. There was a U‐shaped response curve with the greatest effect seen at 0.1 μM concentration. We used Acinetobacter baumannii infection in a neutropenic murine thigh infection model. Plerixafor did not show reduced bacterial growth at 24 h in the mouse thigh model, nor did it amplify the effects of a rifampin antibiotic therapy, in varying regimens. While plerixafor did not mitigate or treat bacterial wound infections in mice, it did reduce sepsis mortality in zebra fish. The observed mortality reduction in our LPS model of zebrafish was consistent with prior research demonstrating a mortality benefit in a murine model of sepsis. However, based on our results, plerixafor is unlikely to be successful as an adjunct therapy for wound infections. Further research is needed to better define the scope of plerixafor as a pathogen‐agnostic therapy. Future directions may include the use of longer acting CXCR4 antagonists, biased CXCR4 signaling, and optimization of animal models.

Introduction: Probability of target attainment (PTA) analysis using Monte Carlo simulations has become a mainstay of dose optimization. We highlight the technical and clinical factors that may affect PTA for beta-lactams. Methods: We performed a mini review in adults to explore factors relating to cefepime PTA success and how researchers incorporate PTA into dosing decisions. In addition, we investigated, via simulations with a population pharmacokinetic (PK) model, factors that may affect cefepime PTA success. Results: The mini review included 14 articles. PTA results were generally consistent, given the differences in patient populations. However, dosing recommendations were more varied and appeared to depend on the definition of pharmacodynamic (PD) target, definition of PTA success and specific clinical considerations. Only 3 of 14 articles performed formal toxicological analysis. Simulations demonstrated that the largest determinants of cefepime PTA were the choice of PD target, continuous vs. intermittent infusion and creatinine clearance. Assumptions for protein binding, steady state vs. first dose, and simulating different sampling schemes may impact PTA success under certain conditions. The choice of one or two compartments had a minimal effect on PTA. Conclusions: PTA results may be similar with different assumptions and techniques. However, dose recommendation may differ significantly based on the selection of PD target, definition of PTA success and considerations specific to a patient population. Demographics and the PK parameters used to simulate time-concentration profiles should be derived from patient data applicable to the purpose of the PTA. There should be strong clinical rationale for dose selection. When possible, safety and toxicity should be considered in addition to PTA success.