Pharmacologic, Surgical, and Device-Based Cardiac Neuromodulation.

The cardiac autonomic nervous system plays a key role in maintaining normal cardiac physiology, and once disrupted, it worsens the cardiac disease states. Neuromodulation therapies have been emerging as new treatment options, and various techniques have been introduced to mitigate autonomic nervous imbalances to help cardiac patients with their disease conditions and symptoms. In this review article, we discuss various neuromodulation techniques used in clinical settings to treat cardiac diseases.

Comparing the Memory Effects of 50-Hz Low-Frequency and 10-kHz High-Frequency Thoracic Spinal Cord Stimulation on Spinal Neural Network in a Myocardial Infarction Porcine Model.

OBJECTIVE: This study evaluated the effects of cessation of both conventional low-frequency (50 Hz) and high-frequency (10 kHz) spinal cord stimulation (SCS) on the cardiospinal neural network activity in pigs with myocardial infarction (MI). The objective is to provide an insight into the memory effect of SCS. MATERIALS AND METHODS: In nine Yorkshire pigs, chronic MI was created by delivering microspheres to the left circumflex coronary artery. Five weeks after MI, anesthetized pigs underwent sternotomy to expose the heart for performing acute ischemia intervention, and laminectomy to expose the T1-T4 spinal regions for extracellular in vivo neural recording and SCS. Cardiac ischemic-sensitive neurons were identified by selective responsiveness to left anterior descending (LAD) coronary artery occlusion. SCS episodes were delivered in a random order between low- (50 Hz) and high- (10 kHz) frequency, for 1 minute, at 90% of the motor threshold current. Neural firing and synchrony of ischemic-sensitive spinal neurons were evaluated before vs after SCS. RESULTS: Using a 64-channel microelectrode array, 2711 spinal neurons were recorded extracellularly. LAD ischemia excited 228 neurons that were labeled as ischemic-responsive neurons. The cessation of 50-Hz SCS caused a higher activation than did inhibition of ischemic-responsive neurons (41 activated vs 19 inhibited), whereas the cessation of 10-kHz SCS caused an opposite response with higher inhibition (11 activated vs 28 inhibited, p < 0.01 vs 50 Hz). Termination of low-frequency SCS caused an increase in ischemic-responsive neuronal firing rate compared with high-frequency SCS (50 Hz: 0.39 Hz ± 0.16 Hz, 10 kHz: -0.11 Hz ± 0.057 Hz, p < 0.01). In addition, SCS delivered at 50 Hz increased the number of synchronized pairs of neurons by 205 pairs, whereas high-frequency SCS decreased the number of synchronized pairs by 345 pairs (p < 0.01). CONCLUSIONS: High-frequency (10 kHz) stimulation provides persistent suppression of the ischemia-sensitive neurons after termination of SCS. In contrast, the spinal neural network reverted to excitatory state after termination of low-frequency (50 Hz) stimulation.

Improving Sensitivity and Longevity of In Vivo Glutamate Sensors with Electrodeposited NanoPt.

In vivo glutamate sensing has provided valuable insight into the physiology and pathology of the brain. Electrochemical glutamate biosensors, constructed by cross-linking glutamate oxidase onto an electrode and oxidizing H2O2 as a proxy for glutamate, are the gold standard for in vivo glutamate measurements for many applications. While glutamate sensors have been employed ubiquitously for acute measurements, there are almost no reports of long-term, chronic glutamate sensing in vivo, despite demonstrations of glutamate sensors lasting for weeks in vitro. To address this, we utilized a platinum electrode with nanometer-scale roughness (nanoPt) to improve the glutamate sensors' sensitivity and longevity. NanoPt improved the GLU sensitivity by 67.4% and the sensors were stable in vitro for 3 weeks. In vivo, nanoPt glutamate sensors had a measurable signal above a control electrode on the same array for 7 days. We demonstrate the utility of the nanoPt sensors by studying the effect of traumatic brain injury on glutamate in the rat striatum with a flexible electrode array and report measurements of glutamate taken during the injury itself. We also show the flexibility of the nanoPt platform to be applied to other oxidase enzyme-based biosensors by measuring γ-aminobutyric acid in the porcine spinal cord. NanoPt is a simple, effective way to build high sensitivity, robust biosensors harnessing enzymes to detect neurotransmitters in vivo.

The effects of alcohol use on smoking cessation treatment with nicotine replacement therapy: An observational study.

INTRODUCTION: Concurrent users of tobacco and alcohol are at greater risk of harm than use of either substance alone. It remains unclear how concurrent tobacco and alcohol use affects smoking cessation across levels of alcohol use and related problems. This study assessed the relationship between smoking cessation and levels of alcohol use problems. METHODS: 59,018 participants received nicotine replacement therapy through a smoking cessation program. Alcohol use and related symptoms were assessed using the Alcohol Use Disorders Identification Test (AUDIT-10) and the AUDIT-Concise (AUDIT-C). The primary outcome was 7-day point prevalence cigarette abstinence (PPA) at 6-month follow-up. We evaluated the association between alcohol use (and related problems) and smoking cessation using descriptive methods and mixed-effects logistic regression. RESULTS: 7-day PPA at 6-months was lower in groups meeting hazardous alcohol consumption criteria, with the lowest probability of smoking abstinence observed in the highest risk group. The probability of successful tobacco cessation fell with increasing levels of alcohol use and related problems. Adjusted predicted probabilities were 30.3 (95 % CI = 29.4, 31.1) for non-users, 30.2 (95 % CI = 29.4, 31.0) for low-risk users, 29.0 (95 % CI = 28.1, 29.9) for those scoring below 8 on the AUDIT-10, 27.3 (95 % CI = 26.0, 28.6) for those scoring 8-14, and 24.4 (95 % CI = 22.3, 26.5) for those scoring 15 or higher. CONCLUSION: Heavy, hazardous alcohol use is associated with lower odds of successfully quitting smoking compared to low or non-use of alcohol. Targeting alcohol treatment to this group may improve tobacco cessation outcomes.

Severe aortic stenosis: secular trends of incidence and outcomes.

BACKGROUND AND AIMS: Severe aortic stenosis (AS) is the guideline-based indication for aortic valve replacement (AVR), which has markedly increased with transcatheter approaches, suggesting possible increasing AS incidence. However, reported secular trends of AS incidence remain contradictory and lack quantitative Doppler echocardiographic ascertainment. METHODS: All adults residents in Olmsted County (MN, USA) diagnosed over 20 years (1997-2016) with incident severe AS (first diagnosis) based on quantitatively defined measures (aortic valve area ≤ 1 cm2, aortic valve area index ≤ 0.6 cm2/m2, mean gradient ≥ 40 mmHg, peak velocity ≥ 4 m/s, Doppler velocity index ≤ 0.25) were counted to define trends in incidence, presentation, treatment, and outcome. RESULTS: Incident severe AS was diagnosed in 1069 community residents. The incidence rate was 52.5 [49.4-55.8] per 100 000 patient-year, slightly higher in males vs. females and was almost unchanged after age and sex adjustment for the US population 53.8 [50.6-57.0] per 100 000 residents/year. Over 20 years, severe AS incidence remained stable (P = .2) but absolute burden of incident cases markedly increased (P = .0004) due to population growth. Incidence trend differed by sex, stable in men (incidence rate ratio 0.99, P = .7) but declining in women (incidence rate ratio 0.93, P = .02). Over the study, AS clinical characteristics remained remarkably stable and AVR performance grew and was more prompt (from 1.3 [0.1-3.3] years in 1997-2000 to 0.5 [0.2-2.1] years in 2013-16, P = .001) but undertreatment remained prominent (>40%). Early AVR was associated with survival benefit (adjusted hazard ratio 0.55 [0.42-0.71], P < .0001). Despite these improvements, overall mortality (3-month 8% and 3-year 36%), was swift, considerable and unabated (all P ≥ .4) throughout the study. CONCLUSIONS: Over 20 years, the population incidence of severe AS remained stable with increased absolute case burden related to population growth. Despite stable severe AS presentation, AVR performance grew notably, but while declining, undertreatment remained substantial and disease lethality did not yet decline. These population-based findings have important implications for improving AS management pathways.

Techniques to Reduce the Rate of Infection in Surgeries for Cerebrospinal Fluid Shunting in Adults.

OBJECTIVE: Cerebrospinal fluid shunt placement is associated with high rates of infection. Multiple standardized protocols, particularly in pediatric populations, have been proposed to mitigate this infection rate. We sought to determine the effectiveness of a standardized shunt infection protocol in a large adult population. METHODS: A retrospective cohort study of adults presenting for primary cerebrospinal fluid shunt placement from 2012 to 2022. The primary outcome of interest was shunt infection. The primary exposure of interest was implementation of the shunt protocol (began October 2015). Secondary exposures of interest included use and type of perioperative antibiotics and total operating room time. RESULTS: In total, 820 patients were included, 140 before protocol implementation and 680 after protocol implementation. The overall number of infections over the study period was 15 (1.8% infection rate), with 8 infections preprotocol (5.7%) and 7 infections during the protocol period (1.0%). The infection protocol was associated with a decreased infection rate (odds rato [OR] 0.18, 95% confidence interval [CI] 0.05-0.58, P = 0.002). Total operating room time (OR 1.38 per 30-minute increase, 95% CI 1.05-1.81, P = 0.021) was associated with increased infection rate. Patients who received antibiotics with primarily gram-positive coverage (cefazolin or equivalent) did not have significantly different odds of shunt infection as patients who received broad-spectrum coverage (OR 2.10, 95% CI 0.56-7.88, P = 0.274). CONCLUSIONS: The implementation of an evidence-based perioperative shunt infection protocol is an effective method to decrease shunt infections. Broad-spectrum perioperative antibiotics may not have greater efficacy than gram-positive only coverage, but more research is required.

Comparative Effectiveness of First-Line and Alternative Antibiotic Regimens in Hospitalized Patients With Nonsevere Community-Acquired Pneumonia: A Multicenter Retrospective Cohort Study.

BACKGROUND: There are several antibiotic regimens to treat community-acquired pneumonia (CAP). RESEARCH QUESTION: In patients hospitalized to a non-ICU ward setting with CAP, is there a difference between first-line and alternative antibiotic regimens (ß-lactam plus macrolide [BL+M], ß-lactam [BL] alone, respiratory fluoroquinolone [FQ], or ß-lactam plus doxycycline [BL+D]) in terms of in-hospital mortality? STUDY DESIGN AND METHODS: This retrospective cohort study included consecutive patients admitted with CAP at 19 Canadian hospitals from 2015 to 2021. Taking a target trial approach, patients were categorized into the four antibiotic groups based on the initial antibiotic treatment within 48 h of admission. Patients with severe CAP requiring ICU admission in the first 48 h were excluded. The primary outcome was all-cause in-hospital mortality. Secondary outcome included time to being discharged alive. Propensity score and overlap weighting were used to balance covariates. RESULTS: Of 23,512 patients, 9,340 patients (39.7%) received BL+M, 9,146 (38.9%) received BL, 4,510 (19.2%) received FQ, and 516 (2.2%) received BL+D. The number of in-hospital deaths was 703 (7.5%) for the BL+M group, 888 (9.7%) for the BL group, 302 (6.7%) for the FQ group, and 31 (6.0%) for the BL+D group. The adjusted risk difference for in-hospital mortality when compared with BL+M was 1.5% (95% CI, -0.3% to 3.3%) for BL, -0.9% (95% CI, -2.9% to 1.1%) for FQ, and -1.9% (95% CI, -4.8% to 0.9%) for BL+D. Compared with BL+M, the subdistribution hazard ratio for being discharged alive was 0.90 (95% CI, 0.84-0.96) for BL, 1.07 (95% CI, 0.99-1.16) for FQ, and 1.04 (95% CI, 0.93-1.17) for BL+D. INTERPRETATION: BL+M, FQ, and BL+D had similar outcomes and can be considered effective regimens for nonsevere CAP. Compared with BL+M, BL was associated with longer time to discharge and the CI for mortality cannot exclude a small but clinically important increase in risk.

Síntesis de glicoconjugados de albúmina sérica bovina y oligosacáridos de quitosano para el análisis de adhesión bacteriana / Synthesis of glycoconjugates of bovine albumin and chitosan oligosaccharides for the analysis of bacterial adhesion / Síntese de glicoconjugados de albumina serica bovina e oligossacarídeos de quitosana para análise de adesão bacteriana

Resumen El aumento de la resistencia a los antibióticos por parte de bacterias patógenas ha motivado la búsqueda de alternativas para disminuir su utilización. Dentro de las opciones propuestas se encuentra la terapia de antiadherencia, en la cual se utilizan moléculas análogas a los glicoepítopes que son reconocidos por las bacterias para impedir la unión de éstas al tejido celular. En este estudio se llevó a cabo la obtención de glicoconjugados por medio de la reacción de Maillard partiendo de albúmina sérica bovina (BSA) y oligosacáridos de quitosano (oligosacáridos sin ultrafiltrar, ultrafiltrados y ultrafiltrados acetilados), en proporción 1:1 (p/p) a tres temperaturas de incubación (50, 60 y 70 °C) por 30 min. La caracterización de los conjugados sintetizados se realizó utilizando electroforesis (SDS-PAGE), espectroscopía de infrarrojo y espectroscopía de fluorescencia. Se realizaron ensayos de reconocimiento usando aglutinina de germen de trigo (WGA) y bacterias [Escherichia coli (K88ac y K88+)]. La caracterización por medio de electroforesis y espectroscopía de infrarrojo evidenció la unión de los oligosacáridos de quitosano a la estructura de la BSA. Además, los ensayos evidenciaron el reconocimiento de las moléculas sintetizadas tanto por la lectina WGA como por las bacterias. Los glicoconjugados sintetizados sin ultrafiltrar ni acetilar mostraron resultados muy favorables en el reconocimiento por ambas bacterias, lo que constituye una ventaja práctica, ya que su implementación a mayor escala reduciría costos de producción

Abstract The increase in antibiotic resistance by pathogenic bacteria has motivated the search for alternatives to reduce the use of antibiotics. Among these alternatives is anti-adhesion therapy, in which molecules that mimic the glycoepitopes that recognise bacteria are used to prevent their binding to cellular tissue. In this study, glycoconjugates were obtained by means of the Maillard reaction starting from bovine serum albumin (BSA) and chitosan oligosaccharides (unfiltered oligosaccharides, ultrafiltered and acetylated ultrafiltered), in a ratio of 1:1 (w/w) at three incubation temperatures (50, 60 and 70 °C) per 30 min. The characterisation was performed using the techniques of electrophoresis (SDS-PAGE), infrared spectroscopy and fluorescence spectroscopy. Recognition assays were performed using wheat germ agglutinin (WGA) and Escherichia coli bacteria (K88ac and K88+). Characterisation by electrophoresis and infrared spectroscopy demonstrated the binding of chitosan oligosaccharides to the structure of BSA. In addition, the tests showed the recognition of the molecules synthesised by both the WGA lectin and the E. coli bacteria. The glycoconjugates synthesised without ultrafiltration or acetylation showed very favourable results in recognition with both bacteria, which is an advantage, since its implementation on a larger scale would reduce production costs.

Resumo O aumento da resistência aos antibióticos por bactérias patogênicas tem motivado a busca de alterna­tivas para reduzir seu uso. Entre essas alternativas está a terapia anti-adesão, na qual são utilizadas moléculas análogas aos glicoepítopos que são reconhecidas pelas bactérias para impedir sua união ao tecido celular. Neste estudo, os glicoconjugados foram obtidos por meio da reação de Maillard a partir de albumina sérica bovina (BSA) e oligossacarídeos de quitosana (oligossacarídeos não ultra­filtrados, ultrafiltrados e acetilados ultrafiltrados), na proporção de 1:1 (p/p) em três temperaturas de incubação (50, 60 e 70 °C) durante 30 min. A caracterização dos conjugados sintetizados foi realizada utilizando a eletroforese (SDS-PAGE), espectroscopia de infravermelho e espectroscopia de fluorescência. Os ensaios de reconhecimento foram realizados utilizando aglutinina de germe de trigo (WGA) e bactérias [Escherichia coli (K88ac e K88+)]. A caracterização por meio de eletroforese e espectroscopia de infravermelho demonstrou a união dos oligossacarídeos de quitosana à estrutura da BSA. Além disso, os testes evidenciaram o reconhecimento das moléculas sintetizadas tanto pela lectina WGA quanto pelas bactérias. Os glicoconjugados sintetizados sem ultrafiltração ou acetilação apresentaram resultados muito favoráveis no reconhecimento por ambas as bactérias, o que é uma vantagem, visto que sua implementação em maior escala reduziria custos de produção.

Role of Artificial Intelligence in Global Surgery: A Review of Opportunities and Challenges.

Global surgery broadly refers to a rapidly expanding multidisciplinary field concerned with providing better and equitable surgical care across international health systems. Global surgery initiatives primarily focus on capacity building, advocacy, education, research, and policy development in low- and middle-income countries (LMICs). The inadequate surgical, anesthetic, and obstetric care currently contributes to 18 million preventable deaths each year. Hence, there is a growing interest in the rapid growth of artificial intelligence (AI) that provides a distinctive opportunity to enhance surgical services in LMICs. AI modalities have been used for personalizing surgical education, automating administrative tasks, and developing realistic and cost-effective simulation-training programs with provisions for people with special needs. Furthermore, AI may assist with providing insights for governance, infrastructure development, and monitoring/predicting stock take or logistics failure that can help in strengthening global surgery pillars. Numerous AI-assisted telemedicine-based platforms have allowed healthcare professionals to virtually assist in complex surgeries that may help to improve surgical accessibility across LMICs. Challenges in implementing AI technology include the misrepresentation of minority populations in the datasets leading to discriminatory bias. Human hesitancy, employment uncertainty, automation bias, and role of confounding factors need to be further studied for equitable utilization of AI. With a focused and evidence-based approach, AI could help several LMICs overcome bureaucratic inefficiency and develop more efficient surgical systems.

Nonviral In Vivo Delivery of CRISPR-Cas9 Using Protein-Agnostic, High-Loading Porous Silicon and Polymer Nanoparticles.

The complexity of CRISPR machinery is a challenge to its application for nonviral in vivo therapeutic gene editing. Here, we demonstrate that proteins, regardless of size or charge, efficiently load into porous silicon nanoparticles (PSiNPs). Optimizing the loading strategy yields formulations that are ultrahigh loading─>40% cargo by volume─and highly active. Further tuning of a polymeric coating on the loaded PSiNPs yields nanocomposites that achieve colloidal stability under cryopreservation, endosome escape, and gene editing efficiencies twice that of the commercial standard Lipofectamine CRISPRMAX. In a mouse model of arthritis, PSiNPs edit cells in both the cartilage and synovium of knee joints, and achieve 60% reduction in expression of the therapeutically relevant MMP13 gene. Administered intramuscularly, they are active over a broad dose range, with the highest tested dose yielding nearly 100% muscle fiber editing at the injection site. The nanocomposite PSiNPs are also amenable to systemic delivery. Administered intravenously in a model that mimics muscular dystrophy, they edit sites of inflamed muscle. Collectively, the results demonstrate that the PSiNP nanocomposites are a versatile system that can achieve high loading of diverse cargoes and can be applied for gene editing in both local and systemic delivery applications.

Spinal neuromodulation mitigates myocardial ischemia-induced sympathoexcitation by suppressing the intermediolateral nucleus hyperactivity and spinal neural synchrony.

Introduction: Myocardial ischemia disrupts the cardio-spinal neural network that controls the cardiac sympathetic preganglionic neurons, leading to sympathoexcitation and ventricular tachyarrhythmias (VTs). Spinal cord stimulation (SCS) is capable of suppressing the sympathoexcitation caused by myocardial ischemia. However, how SCS modulates the spinal neural network is not fully known. Methods: In this pre-clinical study, we investigated the impact of SCS on the spinal neural network in mitigating myocardial ischemia-induced sympathoexcitation and arrhythmogenicity. Ten Yorkshire pigs with left circumflex coronary artery (LCX) occlusion-induced chronic myocardial infarction (MI) were anesthetized and underwent laminectomy and a sternotomy at 4-5 weeks post-MI. The activation recovery interval (ARI) and dispersion of repolarization (DOR) were analyzed to evaluate the extent of sympathoexcitation and arrhythmogenicity during the left anterior descending coronary artery (LAD) ischemia. Extracellular in vivo and in situ spinal dorsal horn (DH) and intermediolateral column (IML) neural recordings were performed using a multichannel microelectrode array inserted at the T2-T3 segment of the spinal cord. SCS was performed for 30 min at 1 kHz, 0.03 ms, 90% motor threshold. LAD ischemia was induced pre- and 1 min post-SCS to investigate how SCS modulates spinal neural network processing of myocardial ischemia. DH and IML neural interactions, including neuronal synchrony as well as cardiac sympathoexcitation and arrhythmogenicity markers were evaluated during myocardial ischemia pre- vs. post-SCS. Results: ARI shortening in the ischemic region and global DOR augmentation due to LAD ischemia was mitigated by SCS. Neural firing response of ischemia-sensitive neurons during LAD ischemia and reperfusion was blunted by SCS. Further, SCS showed a similar effect in suppressing the firing response of IML and DH neurons during LAD ischemia. SCS exhibited a similar suppressive impact on the mechanical, nociceptive and multimodal ischemia sensitive neurons. The LAD ischemia and reperfusion-induced augmentation in neuronal synchrony between DH-DH and DH-IML pairs of neurons were mitigated by the SCS. Discussion: These results suggest that SCS is decreasing the sympathoexcitation and arrhythmogenicity by suppressing the interactions between the spinal DH and IML neurons and activity of IML preganglionic sympathetic neurons.

An initial reliability analysis of a patient counseling rubric to objectively measure student pharmacist performance.

Current literature outlines the documented need for improved communication during patient medication counseling. Although many tools exist, there needs to be a national standardized tool that complies with federal and state law, to objectively measure student pharmacist performance during patient counseling in the community pharmacy setting. The primary objective of this study is to perform an initial analysis of the internal consistency reliability of a patient medication counseling rubric designed with an Indian Health Services theoretical framework. Secondary objectives include measuring changes in student performance over the time of the study. The 18-item rubric was developed to objectively measure student pharmacist performance during patient medication counseling sessions in a 21-h Introductory Pharmacy Practice Experience (IPPE) course. The community-pharmacy-based IPPE patient counseling course evaluates students' communication skills and patient-centered counseling techniques in live and simulated patient counseling sessions. Three pharmacist evaluators assessed a total of 247 student counseling sessions. The rubric's internal consistency reliability was analyzed, and student performance improvement was observed within the course. Students' performance was evaluated as "meets expectations" in most live and simulated sessions. However, an independent groups t-test showed that the mean performance score for the live counseling sessions (2.59, SD = 0.29) was higher (p < 0.001) than that for the simulated counseling sessions (2.35, SD = 0.35). Students' performance in the course improved over three weeks [Week 1: mean (SD) = 2.29 (0.32), Week 2: mean (SD) = 2.44 (0.33), Week 3: mean (SD) = 2.62 (0.29); p < 0.001]. A Tukey-Kramer comparison post hoc test found a significant increase in the mean performance scores between weeks (p < 0.05). The overall internal consistency reliability of the counseling rubric was determined acceptable, with a Cronbach's alpha of 0.75. Further study is required, including the assessment of inter-rater reliability, factor analysis, variable analysis, and use in other states with patient confirmation testing necessary to validate the rubric for use with student pharmacists in the community pharmacy setting.

Dopamine D1 and NMDA receptor co-regulation of protein translation in cultured nucleus accumbens neurons.

Protein translation is essential for some forms of synaptic plasticity. We used nucleus accumbens (NAc) medium spiny neurons (MSN), co-cultured with cortical neurons to restore excitatory synapses, to examine whether dopamine modulates protein translation in NAc MSN. FUNCAT was used to measure translation in MSNs under basal conditions and after disinhibiting excitatory transmission using the GABAA receptor antagonist bicuculline (2 hr). Under basal conditions, translation was not altered by the D1-class receptor (D1R) agonist SKF81297 or the D2-class receptor (D2R) agonist quinpirole. Bicuculline alone robustly increased translation. This was reversed by quinpirole but not SKF81297. It was also reversed by co-incubation with the D1R antagonist SCH23390, but not the D2R antagonist eticlopride, suggesting dopaminergic tone at D1Rs. This was surprising because no dopamine neurons are present. An alternative explanation is that bicuculline activates translation by increasing glutamate tone at NMDA receptors (NMDAR) within D1R/NMDAR heteromers, which have been described in other cell types. Supporting this, immunocytochemistry and proximity ligation assays revealed D1/NMDAR heteromers on NAc cells both in vitro and in vivo. Further, bicuculline's effect was reversed to the same extent by SCH23390 alone, the NMDAR antagonist APV alone, or SCH23390+APV. These results suggest that: 1) excitatory synaptic transmission stimulates translation in NAc MSNs, 2) this is opposed when glutamate activates D1R/NMDAR heteromers, even in the absence of dopamine, and 3) antagonist occupation of D1Rs within the heteromers prevents their activation. Our study is the first to suggest a role for D2 receptors and D1R/NMDAR heteromers in regulating protein translation.

Estimating the euro area output gap using multivariate information and addressing the COVID-19 pandemic.

We estimate the euro area output gap by applying the Beveridge-Nelson decomposition based on a large Bayesian vector autoregression. Our approach incorporates multivariate information through the inclusion of a wide range of variables in the analysis and addresses data issues associated with the COVID-19 pandemic. The estimated output gap lines up well with the CEPR chronology of the business cycle for the euro area and we find that hours worked, more than the unemployment rate, provides the key source of information about labor utilization in the economy, especially in pinning down the depth of the output gap during the COVID-19 recession when the unemployment rate rose only moderately. Our findings confirm that labor market adjustments to the business cycle in the euro area occur more through the intensive, rather than extensive, margin.

Changes in phytochemical content, bioaccesibility and antioxidant capacity of corn tortillas during simulated in vitro gastrointestinal digestion.

There is a little information about the effect of corn process conditions on the bioactive compounds of tortillas during gastrointestinal digestion. Tortillas elaborated with traditional and extrusion nixtamalization process were subjected to in vitro digestion. Extracts recovered from digestion were employed to determine the changes in phytochemicals, bioaccesibility and antioxidant capacity (DPPH, ABTS and FRAP). Digestion contributed to a greater solubilization of phenolic compounds in raw corn and tortillas, especially in the intestinal phase (311.4-583.2 mg GAE/100 g). With bioaccessibility indexes of 162.83 to 960.7 %. Intestinal phase affected the content of anthocyanins, reaching a lower bioaccessibility value than the found in undigested samples (17.90-29.91 %). Even though the traditional white tortilla showed the highest bioaccessibility values, blue tortilla showed a higher antioxidant activity in different phases of digestion. Both tortillas could function as prebiotic agents in the large intestine. Corn-based products are valuable as part of a healthy diet.

GluA2-lacking AMPA receptors in the nucleus accumbens core and shell contribute to the incubation of oxycodone craving in male rats.

One of the most challenging issues in the treatment of substance use disorder, including misuse of opioids such as oxycodone, is persistent vulnerability to relapse, often triggered by cues or contexts previously associated with drug use. In rats, cue-induced craving progressively intensifies ('incubates') during withdrawal from extended-access self-administration of several classes of misused drugs, including the psychostimulants cocaine and methamphetamine. For these psychostimulants, incubation is associated with strengthening of excitatory synapses in the nucleus accumbens (NAc) through incorporation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors that lack the GluA2 subunit and are therefore Ca2+ -permeable (CP-AMPARs). Once CP-AMPAR upregulation occurs, their stimulation is required for expression of incubation. It is not known if a similar mechanism contributes to incubation of oxycodone craving. Using male rats, we established that incubation occurs by withdrawal day (WD) 15 and persists through WD30. Then, using cell-surface biotinylation, we found that surface levels of the AMPAR subunit GluA1 but not GluA2 are elevated in NAc core and shell of oxycodone rats on WD15, although this wanes by WD30. Next, using intra-NAc injection of the selective CP-AMPAR antagonist Naspm before a seeking test, we demonstrate that CP-AMPAR blockade in either subregion decreases oxycodone seeking on WD15 or WD30 (after incubation), but not WD1, and has no effect in saline self-administering animals. The Naspm results suggest CP-AMPARs persist in synapses through WD30 even if total cell surface levels wane. These results suggest that a common neurobiological mechanism contributes to expression of incubation of craving for oxycodone and psychostimulants.

Amyloid-Tau-Neurodegeneration Profiles and Longitudinal Cognition in Sporadic Young-Onset Dementia.

We examined amyloid-tau-neurodegeneration biomarker effects on cognition in a Southeast-Asian cohort of 84 sporadic young-onset dementia (YOD; age-at-onset <65 years) patients. They were stratified into A+N+, A- N+, and A- N- profiles via cerebrospinal fluid amyloid-ß1-42 (A), phosphorylated-tau (T), MRI medial temporal atrophy (neurodegeneration- N), and confluent white matter hyperintensities cerebrovascular disease (CVD). A, T, and CVD effects on longitudinal Mini-Mental State Examination (MMSE) were evaluated. A+N+ patients demonstrated steeper MMSE decline than A- N+ (ß = 1.53; p = 0.036; CI 0.15:2.92) and A- N- (ß = 4.68; p = 0.001; CI 1.98:7.38) over a mean follow-up of 1.24 years. Within A- N+, T- CVD+ patients showed greater MMSE decline compared to T+CVD- patients (ß = - 2.37; p = 0.030; CI - 4.41:- 0.39). A+ results in significant cognitive decline, while CVD influences longitudinal cognition in the A- sub-group.

Metabolic clearance of select opioids and opioid antagonists using hepatic spheroids and recombinant cytochrome P450 enzymes.

The opioid crisis is a pressing public health issue, exacerbated by the emergence of more potent synthetic opioids, particularly fentanyl and its analogs. While competitive antagonists exist, their efficacy against synthetic opioids is largely unknown. Furthermore, due to the short durations of action of current antagonists, renarcotization remains a concern. In this study, metabolic activity was characterized for fentanyl-class opioids and common opioid antagonists using multiple in vitro systems, namely, cytochrome P450 (CYP) enzymes and hepatic spheroids, after which an in vitro-in vivo correlation was applied to convert in vitro metabolic activity to predictive in vivo intrinsic clearance. For all substrates, intrinsic hepatic metabolism was higher than the composite of CYP activities, due to fundamental differences between whole cells and single enzymatic reactions. Of the CYP isozymes investigated, 3A4 yielded the highest absolute and relative metabolism across all substrates, with largely negligible contributions from 2D6 and 2C19. Comparative analysis highlighted elevated lipophilicity and diminished CYP3A4 activity as potential considerations for the development of more efficacious opioid antagonists. Finally, antagonists with a high degree of molecular similarity exhibited comparable clearance, providing a basis for structure-metabolism relationships. Together, these results provide multiple screening criteria for early stage drug discovery involving opioid countermeasures.