State modulation in spatial networks with three interneuron subtypes.

Several inhibitory interneuron subtypes have been identified as critical in regulating sensory responses. However, the specific contribution of each interneuron subtype remains uncertain. In this work, we explore the contributions of cell-type specific activity and synaptic connections to dynamics of a spatially organized spiking neuron network. We find that the firing rates of the somatostatin (SOM) interneurons align closely with the level of network synchrony irrespective of the target of modulatory input. Further analysis reveals that inhibition from SOM to parvalbumin (PV) interneurons must be limited to allow gradual transitions from asynchrony to synchrony and that the strength of recurrent excitation onto SOM neurons determines the level of synchrony achievable in the network. Our results are consistent with recent experimental findings on cell-type specific manipulations. Overall, our results highlight common dynamic regimes achieved across modulations of different cell populations and identify SOM cells as the main driver of network synchrony.

A Network-Based Framework to Discover Treatment-Response-Predicting Biomarkers for Complex Diseases.

The potential of precision medicine to transform complex autoimmune disease treatment is often challenged by limited data availability and inadequate sample size when compared with the number of molecular features found in high-throughput multi-omics data sets. To address this issue, the novel framework PRoBeNet (Predictive Response Biomarkers using Network medicine) was developed. PRoBeNet operates under the hypothesis that the therapeutic effect of a drug propagates through a protein-protein interaction network to reverse disease states. PRoBeNet prioritizes biomarkers by considering i) therapy-targeted proteins, ii) disease-specific molecular signatures, and iii) an underlying network of interactions among cellular components (the human interactome). PRoBeNet helped discover biomarkers predicting patient responses to both an established autoimmune therapy (infliximab) and an investigational compound (a mitogen-activated protein kinase 3/1 inhibitor). The predictive power of PRoBeNet biomarkers was validated with retrospective gene-expression data from patients with ulcerative colitis and rheumatoid arthritis and prospective data from tissues from patients with ulcerative colitis and Crohn disease. Machine-learning models using PRoBeNet biomarkers significantly outperformed models using either all genes or randomly selected genes, especially when data were limited. These results illustrate the value of PRoBeNet in reducing features and for constructing robust machine-learning models when data are limited. PRoBeNet may be used to develop companion and complementary diagnostic assays, which may help stratify suitable patient subgroups in clinical trials and improve patient outcomes.

Distinct dopaminergic spike-timing-dependent plasticity rules are suited to different functional roles.

Various mathematical models have been formulated to describe the changes in synaptic strengths resulting from spike-timing-dependent plasticity (STDP). A subset of these models include a third factor, dopamine, which interacts with the timing of pre- and postsynaptic spiking to contribute to plasticity at specific synapses, notably those from cortex to striatum at the input layer of the basal ganglia. Theoretical work to analyze these plasticity models has largely focused on abstract issues, such as the conditions under which they may promote synchronization and the weight distributions induced by inputs with simple correlation structures, rather than on scenarios associated with specific tasks, and has generally not considered dopamine-dependent forms of STDP. In this paper, we analyze, mathematically and with simulations, three forms of dopamine-modulated STDP in three scenarios that are relevant to corticostriatal synapses. Two of the models considered comprise previously proposed STDP rules with modifications to incorporate dopamine, while the third is a corticostriatal dopamine-dependent STDP rule adapted from a similar one already in the literature. We test the ability of each of the three models to maintain its weights in the face of noise and to complete simple reward prediction and action selection tasks, studying the learned weight distributions and corresponding task performance in each setting. Interestingly, we find that each of the three plasticity rules is well suited to a subset of the scenarios studied but falls short in others. These results show that different tasks may require different forms of synaptic plasticity, yielding the prediction that the precise form of the STDP mechanism may vary across regions of the striatum, and other brain areas impacted by dopamine, that are involved in distinct computational functions.

A novel mechanism for ramping bursts based on slow negative feedback in model respiratory neurons.

Recordings from pre-Bötzinger complex neurons responsible for the inspiratory phase of the respiratory rhythm reveal a ramping burst pattern, starting around the time that the transition from expiration to inspiration begins, in which the spike rate gradually rises until a transition into a high-frequency burst occurs. The spike rate increase along the burst is accompanied by a gradual depolarization of the plateau potential that underlies the spikes. These effects may be functionally important for inducing the onset of inspiration and hence maintaining effective respiration; however, most mathematical models for inspiratory bursting do not capture this activity pattern. Here, we study how the modulation of spike height and afterhyperpolarization via the slow inactivation of an inward current can support various activity patterns including ramping bursts. We use dynamical systems methods designed for multiple timescale systems, such as bifurcation analysis based on timescale decomposition and averaging over fast oscillations, to generate an understanding of and predictions about the specific dynamic effects that lead to ramping bursts. We also analyze how transitions between ramping and other activity patterns may occur with parameter changes, which could be associated with experimental manipulations, environmental conditions, and/or development.

How cortico-basal ganglia-thalamic subnetworks can shift decision policies to maximize reward rate.

All mammals exhibit flexible decision policies that depend, at least in part, on the cortico-basal ganglia-thalamic (CBGT) pathways. Yet understanding how the complex connectivity, dynamics, and plasticity of CBGT circuits translates into experience-dependent shifts of decision policies represents a longstanding challenge in neuroscience. Here we used a computational approach to address this problem. Specifically, we simulated decisions driven by CBGT circuits under baseline, unrewarded conditions using a spiking neural network, and fit the resulting behavior to an evidence accumulation model. Using canonical correlation analysis, we then replicated the existence of three recently identified control ensembles (responsiveness, pliancy and choice) within CBGT circuits, with each ensemble mapping to a specific configuration of the evidence accumulation process. We subsequently simulated learning in a simple two-choice task with one optimal (i.e., rewarded) target. We find that value-based learning, via dopaminergic signals acting on cortico-striatal synapses, effectively manages the speed-accuracy tradeoff so as to increase reward rate over time. Within this process, learning-related changes in decision policy can be decomposed in terms of the contributions of each control ensemble, and these changes are driven by sequential reward prediction errors on individual trials. Our results provide a clear and simple mechanism for how dopaminergic plasticity shifts specific subnetworks within CBGT circuits so as to strategically modulate decision policies in order to maximize effective reward rate.

Breast Cancer-Related Lymphedema Results in Impaired Epidermal Differentiation and Tight Junction Dysfunction.

Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of FLG and the tight junction protein ZO-1 in skin affected by moderate lymphedema or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to those in the controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that similar to the clinical scenario, the expression of skin barrier proteins was decreased relative to that in normal skin and that colonization with Staphylococcus epidermidis bacteria amplified this effect as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema.

Color Flow Ultrasound Spatial Sampling Beam Density for Partial Volume-Corrected Three-Dimensional Volume Flow (3DVF): Theory, Simulation, and Experiment.

OBJECTIVE: The purpose of this study was to quantify the accuracy of partial volume-corrected three-dimensional volume flow (3DVF) measurements as a function of spatial sampling beam density using carefully-designed parametric analyses in order to inform the target applications of 3DVF. METHODS: Experimental investigations employed a mechanically-swept curvilinear ultrasound array to acquire 3D color flow (6.3 MHz) images in flow phantoms consisting of four lumen diameters (6.35, 4.88, 3.18 and 1.65 mm) with volume flow rates of 440, 260, 110 and 30 mL/min, respectively. Partial volume-corrected three-dimensional volume flow (3DVF) measurements, based on the Gaussian surface integration principle, were computed at five regions of interest positioned between depths of 2 and 6 cm in 1 cm increments. At each depth, the color flow beam point spread function (PSF) was also determined, using in-phase/quadrature data, such that 3DVF bias could then be related to spatial sampling beam density. Corresponding simulations were performed for a laminar parabolic flow profile that was sampled using the experimentally-measured PSFs. Volume flow was computed for all combinations of lumen diameters and the PSFs at each depth. RESULTS: Accurate 3DVF measurements, i.e., bias less than ±20%, were achieved for spatial sampling beam densities where at least 6 elevational color flow beams could be positioned across the lumen. In these cases, greater than 8 lateral color flow beams were present. PSF measurements showed an average lateral-to-elevational beam width asymmetry of 1:2. Volume flow measurement bias increased as the color flow beam spatial sampling density within the lumen decreased. CONCLUSION: Applications of 3DVF, particularly those in the clinical domain, should focus on areas where a spatial sampling density of 6 × 6 (lateral x elevational) beams can be realized in order to minimize measurement bias. Matrix-based ultrasound arrays that possess symmetric PSFs may be advantageous to achieve adequate beam densities in smaller vessels.

Severity Of Radiographic Osteoarthritis: Association with Improved Patient Reported Outcomes Following Knee Arthroplasty.

INTRODUCTION: The Kellgren and Lawrence (KL) classification for knee osteoarthritis estimates disease severity. Its utility in predicting patient-reported outcomes (PROs) after primary total knee arthroplasty (pTKA) has been suggested. We hypothesized that patients who had higher preoperative KL grades would demonstrate greater improvements in PROs after pTKA. METHODS: This was a retrospective review of patients who underwent pTKA between 2016 and 2021. Two observers graded preoperative radiographs (KL1/2, KL3, and KL4). Knee Injury and Osteoarthritis Outcome Score (KOOS) for activities of daily living (KOOS-ADL) and pain (KOOS-Pain) were collected at preoperative and 12-month postoperative visits. Changes in KOOS-ADL (ΔADL) and changes in KOOS-Pain (ΔPain) scores were compared from the preoperative to 12-month postoperative mark across different groups, with the minimal clinically important difference (MCID) for both ΔADL (MCID-ADL) and ΔPain (MCID-Pain) also being calculated. A P-value of < 0.05 was considered statistically significant. RESULTS: A total of 1651 patients were included in the study. The KL3 and KL4 groups exhibited significantly higher ΔADL scores and ΔPain scores compared with the KL1/2 group (P < 0.01). Patients who had KL3 and KL4 were 1.42 (P = 0.03) and 1.88 (P < 0.01) times, respectively, more likely to achieve MCID-ADL compared with those who had KL1/2. Furthermore, patients who had a KL4 were 1.92 times (P < 0.01) more likely to reach MCID-Pain compared with those who had KL1/2. CONCLUSIONS: This study determined that patients who had higher preoperative KL grades experienced markedly greater improvements in KOOS-ADL and KOOS-Pain scores than those who had lower KL grades. These findings offer surgeons an objective tool when counseling patients on expected outcomes after pTKA.

Arkypallidal neurons in the external globus pallidus can mediate inhibitory control by altering competition in the striatum.

Reactive inhibitory control is crucial for survival. Traditionally, this control in mammals was attributed solely to the hyperdirect pathway, with cortical control signals flowing unidirectionally from the subthalamic nucleus (STN) to basal ganglia output regions. Yet recent findings have put this model into question, suggesting that the STN is assisted in stopping actions through ascending control signals to the striatum mediated by the external globus pallidus (GPe). Here we investigate this suggestion by harnessing a biologically-constrained spiking model of the corticobasal ganglia-thalamic (CBGT) circuit that includes pallidostriatal pathways originating from arkypallidal neurons. Through a series of experiments probing the interaction between three critical inhibitory nodes (the STN, arkypallidal cells, and indirect path-way spiny projection neurons), we find that the GPe acts as a critical mediator of both ascending and descending inhibitory signals in the CBGT circuit. In particular, pallidostriatal pathways regulate this process by weakening the direct pathway dominance of the evidence accumulation process driving decisions, which increases the relative suppressive influence of the indirect pathway on basal ganglia output. These findings delineate how pallidostriatal pathways can facilitate action cancellation by managing the bidirectional flow of information within CBGT circuits.

Dopamine depletion weakens direct pathway modulation of SNr neurons.

Neurons in the substantia nigra reticulata (SNr) transmit information about basal ganglia output to dozens of brain regions in thalamocortical and brainstem motor networks. Activity of SNr neurons is regulated by convergent input from upstream basal ganglia nuclei, including GABAergic inputs from the striatum and the external globus pallidus (GPe). GABAergic inputs from the striatum convey information from the direct pathway, while GABAergic inputs from the GPe convey information from the indirect pathway. Chronic loss of dopamine, as occurs in Parkinson's disease, disrupts the balance of direct and indirect pathway neurons at the level of the striatum, but the question of how dopamine loss affects information propagation along these pathways outside of the striatum is less well understood. Using a combination of in vivo and slice electrophysiology, we find that dopamine depletion selectively weakens the direct pathway's influence over neural activity in the SNr due to changes in the decay kinetics of GABA-mediated synaptic currents. GABAergic signaling from GPe neurons in the indirect pathway was not affected, resulting in an inversion of the normal balance of inhibitory control over basal ganglia output through the SNr. These results highlight the contribution of cellular mechanisms outside of the striatum that impact the responses of basal ganglia output neurons to the direct and indirect pathways in disease.

Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson's disease.

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations.

Comment on Barbieri et al. Umbilical Vein Blood Flow in Uncomplicated Pregnancies: Systematic Review of Available Reference Charts and Comparison with a New Cohort. J. Clin. Med. 2023, 12, 3132.

We would like to comment on the systemic review article published in the Journal of Clinical Medicine by Barbieri et al [...].

Rethinking the external globus pallidus and information flow in cortico-basal ganglia-thalamic circuits.

For decades, the external globus pallidus (GPe) has been viewed as a passive way-station in the indirect pathway of the cortico-basal ganglia-thalamic (CBGT) circuit, sandwiched between striatal inputs and basal ganglia outputs. According to this model, one-way descending striatal signals in the indirect pathway amplify the suppression of downstream thalamic nuclei by inhibiting GPe activity. Here, we revisit this assumption, in light of new and emerging work on the cellular complexity, connectivity and functional role of the GPe in behaviour. We show how, according to this new circuit-level logic, the GPe is ideally positioned for relaying ascending and descending control signals within the basal ganglia. Focusing on the problem of inhibitory control, we illustrate how this bidirectional flow of information allows for the integration of reactive and proactive control mechanisms during action selection. Taken together, this new evidence points to the GPe as being a central hub in the CBGT circuit, participating in bidirectional information flow and linking multifaceted control signals to regulate behaviour.

Introducing the STReaC (Spike Train Response Classification) toolbox.

Background: This work presents a toolbox that implements methodology for automated classification of diverse neural responses to optogenetic stimulation or other changes in conditions, based on spike train recordings. New Method: The toolbox implements what we call the Spike Train Response Classification algorithm (STReaC), which compares measurements of activity during a baseline period with analogous measurements during a subsequent period to identify various responses that might result from an event such as introduction of a sustained stimulus. The analyzed response types span a variety of patterns involving distinct time courses of increased firing, or excitation, decreased firing, or inhibition, or combinations of these. Excitation (inhibition) is identified from a comparative analysis of the spike density function (interspike interval function) for the baseline period relative to the corresponding function for the response period. Results: The STReaC algorithm as implemented in this toolbox provides a user-friendly, tunable, objective methodology that can detect a variety of neuronal response types and associated subtleties. We demonstrate this with single-unit neural recordings of rodent substantia nigra pars reticulata (SNr) during optogenetic stimulation of the globus pallidus externa (GPe). Comparison with existing methods: In several examples, we illustrate how the toolbox classifies responses in situations in which traditional methods (spike counting and visual inspection) either fail to detect a response or provide a false positive. Conclusions: The STReaC toolbox provides a simple, efficient approach for classifying spike trains into a variety of response types defined relative to a period of baseline spiking.

Measurement of Cerebral Metabolism Under Non-Chronic Hemodynamic Conditions.

BACKGROUND: Blood flow to the brain is a critical physiological function and is useful to monitor in critical care settings. Despite that, a surrogate is most likely measured instead of actual blood flow. Such surrogates include velocity measurements in the carotid artery and systemic blood pressure, even though true blood flow can actually be obtained using MRI and other modalities. Ultrasound is regularly used to measure blood flow and is, under certain conditions, able to provide quantitative volumetric blood flow in milliliters per minute. Unfortunately, most times the resulting flow data is not valid due to unmet assumptions (such as flow profile and angle correction). Color flow, acquired in three dimensions, has been shown to yield quantitative blood flow without any assumptions (3DVF). METHODS: Here we are testing whether color flow can perform during physiological conditions common to severe injury. Specifically, we are simulating severe traumatic brain injury (epidural hematoma) as well as hemorrhagic shock with 50% blood loss. Blood flow was measured in the carotid artery of a cohort of 7 Yorkshire mix pigs (40-60 kg) using 3DVF (4D16L, LOGIQ 9, GE HealthCare, Milwaukee, WI, USA) and compared to an invasive flow meter (TS420, Transonic Systems Inc., Ithaca, NY, USA). RESULTS: Six distinct physiological conditions were achieved: baseline, hematoma, baseline 2, hemorrhagic shock, hemorrhagic shock plus hematoma, and post-hemorrhage resuscitation. Mean cerebral oxygen extraction ratio varied from 40.6% ± 13.0% of baseline to a peak of 68.4% ± 15.6% during hemorrhagic shock. On average 3DVF estimated blood flow with a bias of -9.6% (-14.3% root mean squared error) relative to the invasive flow meter. No significant flow estimation error was detected during phases of flow reversal, that was seen in the carotid artery during traumatic conditions. The invasive flow meter showed a median error of -11.5% to 39.7%. CONCLUSIONS: Results suggest that absolute volumetric carotid blood flow to the brain can be obtained and potentially become a more specific biomarker related to cerebral hemodynamics than current surrogate markers.

Risk Factors for Increased Hospital Costs for Primary Total Hip Arthroplasty.

BACKGROUND: Patient medical complexity increases the cost of primary total hip arthroplasty (THA). The goal of this study was to quantify the impact of specific medical comorbidities on the real hospital cost of primary THA. METHODS: This study consisted of a retrospective analysis of 1,222 patient encounters for Current Procedural Terminology code 27130 (primary THA) between January 2017 and March 2020 at a high-volume urban academic medical center. Patient demographics, comorbidities, and admission data were collected, and univariate and multivariate gamma regression analyses were performed to identify associations with increased costs incurred during THA admission. RESULTS: The median total cost for THA was $30,580. Univariate analysis showed increased cost for body mass index (BMI) > 35 versus BMI < 35 ($31,739 versus 30,071; P < .05), American Society of Anesthesiologists (ASA) score 3 to 4 versus ASA 1 to 2 ($32,268 versus 30,045; P < .05), prevalence of diabetes ($31,523 versus 30,379; P < .05), congestive heart failure ($34,814 versus 30,584; P < .05), peripheral vascular disease (PVD) ($35,369 versus 30,573; P < .05), chronic pulmonary disease (CPD) ($34,625 versus 30,405; P < .05), renal disease ($31,973 versus 30,352; P < .05), and increased length of stay (r = 0.424; P < .05). Multivariate gamma regression showed that BMI > 35 (relative risk [RR] = 1.05), ASA 3 to 4 (RR = 1.07), PVD (RR = 1.29), CPD (RR = 1.13), and renal disease (RR = 1.09) were independently associated with increased THA hospital cost (P < .01). Increased costs seen in BMI > 35 versus BMI < 35 patients were largely due to hospital room and board ($6,345 versus 5,766; P = .01) and operating room costs ($5,744 versus 5,185; P < .05). CONCLUSIONS: A BMI > 35, PVD, CPD, renal disease, and ASA 3 to 4 are associated with higher inpatient hospital costs for THA. LEVEL OF EVIDENCE: Level III; Retrospective cohort study.

Diagnostically distinct resting state fMRI energy distributions: A subject-specific maximum entropy modeling study.

Objective: Existing neuroimaging studies of psychotic and mood disorders have reported brain activation differences (first-order properties) and altered pairwise correlation-based functional connectivity (second-order properties). However, both approaches have certain limitations that can be overcome by integrating them in a pairwise maximum entropy model (MEM) that better represents a comprehensive picture of fMRI signal patterns and provides a system-wide summary measure called energy. This study examines the applicability of individual-level MEM for psychiatry and identifies image-derived model coefficients related to model parameters. Method: MEMs are fit to resting state fMRI data from each individual with schizophrenia/schizoaffective disorder, bipolar disorder, and major depression (n=132) and demographically matched healthy controls (n=132) from the UK Biobank to different subsets of the default mode network (DMN) regions. Results: The model satisfactorily explained observed brain energy state occurrence probabilities across all participants, and model parameters were significantly correlated with image-derived coefficients for all groups. Within clinical groups, averaged energy level distributions were higher in schizophrenia/schizoaffective disorder but lower in bipolar disorder compared to controls for both bilateral and unilateral DMN. Major depression energy distributions were higher compared to controls only in the right hemisphere DMN. Conclusions: Diagnostically distinct energy states suggest that probability distributions of temporal changes in synchronously active nodes may underlie each diagnostic entity. Subject-specific MEMs allow for factoring in the individual variations compared to traditional group-level inferences, offering an improved measure of biologically meaningful correlates of brain activity that may have potential clinical utility.

Viloxazine Increases Extracellular Concentrations of Norepinephrine, Dopamine, and Serotonin in the Rat Prefrontal Cortex at Doses Relevant for the Treatment of Attention-Deficit/Hyperactivity Disorder.

Background: Viloxazine ER (viloxazine extended-release capsules; Qelbree®), a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment, has known activity as a norepinephrine (NE) transporter (NET) inhibitor. In vitro studies have also shown direct pharmacological effects on specific serotonin (5-HT) receptors, but not on the serotonin transporter (SERT). An in vivo microdialysis study in rats showed viloxazine (50 mg/kg i.p.) increased extracellular 5-HT, NE, and dopamine (DA) in the prefrontal cortex (PFC), a key brain region in ADHD pathology. This study evaluated whether these effects occur at clinically relevant concentrations. Methods: Microdialysis experiments were conducted in freely-moving, Sprague-Dawley rats (males, 8 weeks). Viloxazine (1, 3, 10, 30 mg/kg) was administered intraperitoneally to establish the dose range in rats at which viloxazine plasma concentrations aligned with those of individuals with ADHD administered therapeutic doses of viloxazine ER. Concentrations of unbound viloxazine, NE, 5-HT, DA, and NE and 5-HT metabolites (3,5-dihydroxyphenylglycol [DHPG] and 5-hydroxyindoleacetic acid [5-HIAA]) were measured in PFC interstitial fluid. After identifying a therapeutically relevant dose (30 mg/kg), the experiment was repeated using 30 and 50 mg/kg viloxazine (as 50 mg/kg increased NE, 5-HT, and DA in prior studies). Results: Viloxazine unbound (free drug) plasma concentrations in rats at 30 mg/kg were comparable to free drug concentrations in individuals with ADHD taking clinically effective doses (based on validated population PK models). Viloxazine 30 mg/kg significantly increased extracellular NE, 5-HT, and DA PFC levels compared to vehicle. Concomitant decreases in DHPG, but not 5-HIAA, support the inhibitory effect of viloxazine on NET but not SERT. Conclusion: At clinically relevant concentrations, viloxazine increases PFC NE, DA, and 5-HT. Prefrontal augmentation of 5-HT does not appear to result from 5-HT reuptake inhibition but may be related to activation of 5-HT neurons. The potential therapeutic role of serotonergic effects in ADHD treatment merits further exploration.

Social Media Use and Its Impact on Physician Review Website Ratings in Hip and Knee Arthroplasty.

BACKGROUND: The growth in social media (SM) use and consumer-driven health care has led more patients to rate surgeons on physician review websites (PRWs). This study assessed surgeon's professional SM presence and its relationship to PRW ratings. METHODS: This was a cross-sectional study of the American Association of Hip and Knee Surgeons members as of June 15, 2021. The presence of SM (Facebook, Twitter, Instagram, YouTube, LinkedIn, ResearchGate, and personal professional website) and PRW (Google [G], Healthgrades [HG], and Vitals [V]) ratings were collected. Statistical analyses compared PRW ratings among surgeons who did and did not have Any SM, defined as having at least one of the following SM accounts: Facebook; Twitter; Instagram; or YouTube. RESULTS: Of the 2,455 surgeons, 550 (22%) had Any SM. Compared to surgeons who did not have Any SM, surgeons who had Any SM had significantly higher G, HG, and V overall scores (G:4.1 versus 3.7; HG:4.3 versus 4.1; V:4.0 versus 3.8; P < .01), number of ratings (G:36.9 versus 26.5; HG:56.8 versus 38.3; V:45.6 versus 30.9; P < .01), and number of comments (G:24.4 versus 16.4; HG:35.2 versus 22.0; V:21.5 versus 12.3; P < .01). Surgeons who had Any SM were 1.8 (1.4 to 2.3; P < .01), 1.5 (1.2 to 1.9; P < .01), and 1.5 (1.2 to 1.9; P < .01) times more likely to have a G, HG, and V score of ≥4.0, respectively, than surgeons who did not have Any SM. CONCLUSIONS: Surgeons who had Any SM demonstrated a significant association with higher PRW overall scores, number of ratings, and number of comments, suggesting that SM presence may increase surgeon PRW ratings.