Impact of COVID-19 on patients undergoing scheduled procedures for chronic venous disease.

OBJECTIVE: The COVID-19 pandemic has drastically altered the medical landscape. Various strategies have been employed to preserve hospital beds, personal protective equipment, and other resources to accommodate the surges of COVID-19 positive patients, hospital overcapacities, and staffing shortages. This has had a dramatic effect on vascular surgical practice. The objective of this study is to analyze the impact of the COVID-19 pandemic on surgical delays and adverse outcomes for patients with chronic venous disease scheduled to undergo elective operations. METHODS: The Vascular Surgery COVID-19 Collaborative (VASCC) was founded in March 2020 to evaluate the outcomes of patients with vascular disease whose operations were delayed. Modules were developed by vascular surgeon working groups and tested before implementation. A data analysis of outcomes of patients with chronic venous disease whose surgeries were postponed during the COVID-19 pandemic from March 2020 through February 2021 was performed for this study. RESULTS: A total of 150 patients from 12 institutions in the United States were included in the study. Indications for venous intervention were: 85.3% varicose veins, 10.7% varicose veins with venous ulceration, and 4.0% lipodermatosclerosis. One hundred two surgeries had successfully been completed at the time of data entry. The average length of the delay was 91 days, with a median of 78 days. Delays for venous ulceration procedures ranged from 38 to 208 days. No patients required an emergent intervention due to their venous disease, and no patients experienced major adverse events following their delayed surgeries. CONCLUSIONS: Interventions may be safely delayed for patients with venous disease requiring elective surgical intervention during the COVID-19 pandemic. This finding supports the American College of Surgeons' recommendations for the management of elective vascular surgical procedures. Office-based labs may be safe locations for continued treatment when resources are limited. Although the interventions can be safely postponed, the negative impact on quality of life warrants further investigation.

Adolescent exposure to sucrose increases cocaine-mediated behaviours in adulthood via Smad3.

Adolescence, a critical period of developmental period, is marked by neurobiological changes influenced by environmental factors. Here, we show how exposure to sucrose, which is ubiquitously available in modern diets, results in changes in behavioural response to cocaine as an adult. Rats were given daily access to either 10% sucrose or water during the adolescent period (PND28-42). Following this period, rats are left undisturbed until they reach adulthood. In adulthood, rats were tested for (i) acquisition of a low dose of cocaine, (ii) progressive ratio (PR) test, and (iii) resistance to punished cocaine taking. Sucrose exposure resulted in significant alterations in all behavioural measures. To determine the neurobiological mechanisms leading to such behavioural adaptations, we find that adolescent sucrose exposure results in an upregulation of the transcription factor Smad3 in the nucleus accumbens (NAc) when compared with water-exposed controls. Transiently blocking the active form of this transcription factor (HSV-dnSmad3) during adolescence mitigated the enhanced cocaine vulnerability-like behaviours observed in adulthood. These findings suggest that prior exposure to sucrose during adolescence can heighten the reinforcing effects of cocaine. Furthermore, they identify the TGF-beta pathway and Smad3 as playing a key role in mediating enduring and long-lasting adaptations that contribute to sucrose-induced susceptibility to cocaine. Taken together, these results have important implications for development and suggest that adolescent sucrose exposure may persistently enhance the susceptibility to substance abuse.

Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans.

Under oxidative stress conditions, hydroxyl radicals can oxidize the phenyl ring of phenylalanine, producing the abnormal tyrosine isomer meta-tyrosine (m-tyrosine). m-Tyrosine levels are commonly used as a biomarker of oxidative stress, and its accumulation has recently been reported to adversely affect cells, suggesting a direct role for m-tyrosine in oxidative stress effects. We found that the Caenorhabditis elegans ortholog of tyrosine aminotransferase (TATN-1)-the first enzyme involved in the metabolic degradation of tyrosine-is up-regulated in response to oxidative stress and directly activated by the oxidative stress-responsive transcription factor SKN-1. Worms deficient in tyrosine aminotransferase activity displayed increased sensitivity to multiple sources of oxidative stress. Biochemical assays revealed that m-tyrosine is a substrate for TATN-1-mediated deamination, suggesting that TATN-1 also metabolizes m-tyrosine. Consistent with a toxic effect of m-tyrosine and a protective function of TATN-1, tatn-1 mutant worms exhibited delayed development, marked reduction in fertility, and shortened lifespan when exposed to m-tyrosine. A forward genetic screen identified a mutation in the previously uncharacterized gene F01D4.5-homologous with human transcription factor 20 (TCF20) and retinoic acid-induced 1 (RAI1)-that suppresses the adverse phenotypes observed in m-tyrosine-treated tatn-1 mutant worms. RNA-Seq analysis of F01D4.5 mutant worms disclosed a significant reduction in the expression of specific isoforms of genes encoding ribosomal proteins, suggesting that alterations in protein synthesis or ribosome structure could diminish the adverse effects of m-tyrosine. Our findings uncover a critical role for tyrosine aminotransferase in the oxidative stress response via m-tyrosine metabolism.

Relationship between Substance Use and Socioeconomic Variables in Pennsylvania Adolescents: 2009-2017.

Purpose: The goal of the current study is to analyze the substance use trends in Generation Z youth (in both middle and high school environments) and to determine if any correlation exists between substance use behaviors and demographic variables. Methods: Analysis is based on substance use data collected through the Pennsylvania Youth Survey (PAYS) from 2009 to 2017 and the 2016 US census data. Results: Our results suggest that substance use in Gen Z adolescents is mainly linked to alcohol, marijuana, cigarettes, smokeless tobacco, vaping, and narcotic prescription drugs. Alcohol is the most prevalent high-risk substance used by 12th grade students with 69.8% of students having consumed alcohol over their lifetime. Vaping is the next highly used substance with 28.9% of students in 12th grade having vaped 30 day prior to the survey. There is a significant correlation among adolescents between smoking cigarettes and using smokeless tobacco. A student using either alcohol, cigarettes or smokeless tobacco is highly likely to use the other two substances as well. Adolescents from counties with a high Caucasian population were at high risk for cigarette and smokeless tobacco use, while the opposite held true for counties with a high number of foreign-born persons or higher Asian or Hispanic populations. Higher median household incomes and higher adult education levels in a county were both protective factors against smokeless tobacco use. Conclusions: Results of the study suggest that students start experimenting with high-risk substance use in early grades and to combat the prevalence, we suggest the importance of educating adolescents of the dangers of drug use in early grades.

Extracellular polyphosphate signals through Ras and Akt to prime Dictyostelium discoideum cells for development.

Linear chains of five to hundreds of phosphates called polyphosphate are found in organisms ranging from bacteria to humans, but their function is poorly understood. In Dictyostelium discoideum, polyphosphate is used as a secreted signal that inhibits cytokinesis in an autocrine negative feedback loop. To elucidate how cells respond to this unusual signal, we undertook a proteomic analysis of cells treated with physiological levels of polyphosphate and observed that polyphosphate causes cells to decrease levels of actin cytoskeleton proteins, possibly explaining how polyphosphate inhibits cytokinesis. Polyphosphate also causes proteasome protein levels to decrease, and in both Dictyostelium and human leukemia cells, decreases proteasome activity and cell proliferation. Polyphosphate also induces Dictyostelium cells to begin development by increasing expression of the cell-cell adhesion molecule CsA (also known as CsaA) and causing aggregation, and this effect, as well as the inhibition of proteasome activity, is mediated by Ras and Akt proteins. Surprisingly, Ras and Akt do not affect the ability of polyphosphate to inhibit proliferation, suggesting that a branching pathway mediates the effects of polyphosphate, with one branch affecting proliferation, and the other branch affecting development.

Pumping the brakes: rostromedial tegmental inhibition of compulsive cocaine seeking.

Addiction is marked by aberrant decision-making and an inability to suppress inappropriate and often dangerous behaviors. We previously demonstrated that inactivation of the rostromedial tegmental nucleus (RMTg) in rats causes persistent food seeking despite impending aversive footshock, an effect strikingly similar to the punishment resistance observed in people with a history of protracted drug use [1]. Here, we extend these studies to demonstrate chemogenetic silencing of RMTg axonal projections to the ventral tegmental area (VTA) (RMTg→VTA pathway) causes rats to endure significantly more footshock to receive cocaine infusions. To further test whether activation of this circuit is sufficient to suppress reward seeking in the absence of an overtly aversive stimulus, we used temporally specific optogenetic stimulation of the RMTg→VTA pathway as a "punisher" in place of footshock following lever pressing for either food or cocaine reward. While optical stimulation of the RMTg→VTA pathway robustly suppressed lever pressing for food, we found that stimulation of this circuit had only modest effects on suppressing responding for cocaine infusions. Even though optical RMTg→VTA stimulation was not particularly effective at reducing ongoing cocaine use, this experience nevertheless had long-lasting consequences, as reinstatement of drug seeking in response to cocaine-associated cues was profoundly suppressed when tested nearly two weeks later. These results suggest the RMTg may serve as a useful target for producing enduring reductions in drug craving, particularly during periods of abstinence from drug use.

Stakeholder perspectives on education in aortic dissection.

The Aortic Dissection (AD) Collaborative was established to evaluate patient-centered research priorities in AD. Education was identified as a topic of interest by the stakeholders. The AD Collaborative Education Working Group evaluated existing educational resources and identified areas amenable to comparative effectiveness research. The most important positive qualities of available AD education resources are ease of use, diversity of representation, accessibility, and organization. The most important negative qualities of these resources are non-patient-centered language, promotional themes, and those with limited applicability and accessibility. Through a series of focus groups, the Working Group identified target audiences for AD education and educational material content and critically assessed and prioritized barriers to effective AD education. Both the target audiences and the barriers include clinicians and patients themselves. The Working Group defined initiatives to overcome barriers, to include a comprehensive, universally agreed on AD resource that is updated in real time and making education accessible to all relevant target audiences. The Working Group then prioritized needs for comparative effectiveness research in AD education and determined that clinician education is the top priority for future efforts. The Working Group determined that assessment and evaluation of specific and appropriate screening strategies is the second most important priority. Finally, the Working Group identified patient education as the third most important priority, specifically determining how patients and their support groups learn best, the ideal strategies for information dissemination, and methods of assessing understanding and satisfaction with the education process.

Sexually dimorphic prelimbic cortex mechanisms play a role in alcohol dependence: protection by endostatin.

Angiogenesis or proliferation of endothelial cells plays a role in brain microenvironment homeostasis. Previously we have shown enhanced expression of markers of angiogenesis in the medial prefrontal cortex during abstinence in an animal model of ethanol dependence induced by chronic intermittent ethanol vapor (CIE) and ethanol drinking (ED) procedure. Here we report that systemic injections of the angiogenesis inhibitor endostatin reduced relapse to drinking behavior in female CIE-ED rats without affecting relapse to drinking in male CIE-ED rats, and female and male nondependent ED rats. Endostatin did not alter relapse to sucrose drinking in both sexes. Endostatin reduced expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) in all groups; however, rescued expression of tight junction protein claudin-5 in the prelimbic cortex (PLC) of female CIE-ED rats. In both sexes, CIE-ED enhanced microglial activation in the PLC and this was selectively prevented by endostatin in female CIE-ED rats. Endostatin prevented CIE-ED-induced enhanced NF-kB activity and expression and Fos expression in females and did not alter reduced Fos expression in males. Analysis of synaptic processes within the PLC revealed sexually dimorphic adaptations, with CIE-ED reducing synaptic transmission and altering synaptic plasticity in the PLC in females, and increasing synaptic transmission in males. Endostatin prevented the neuroadaptations in the PLC in females via enhancing phosphorylation of CaMKII, without affecting the neuroadaptations in males. Our multifaceted approach is the first to link PLC endothelial cell damage to the behavioral, neuroimmune, and synaptic changes associated with relapse to ethanol drinking in female subjects, and provides a new therapeutic strategy to reduce relapse in dependent subjects.