Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI.

Recent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit.

Targeting α1- and α2-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression.

This study assessed the ability of α1 and α2-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α1 agonist phenylephrine, (5) α1 antagonist prazosin, (6) α1D antagonist BMY-7378, (7) α2 agonist clonidine, (8) α2 antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression. While the α1 drugs did not alter the effects of fentanyl, clonidine dose-dependently decreased locomotion and respiration with and without fentanyl. Conversely, yohimbine given at a low dose (0.3-1 mg/kg) stimulated ventilation when given alone and higher doses (>1 mg/kg) partially reversed (∼50 %) fentanyl-induced ventilatory depression, but not locomotor depression. High doses of yohimbine in combination with a suboptimal dose of naltrexone reversed fentanyl-induced ventilatory depression, suggestive of additivity. Yohimbine may serve as an effective adjunctive countermeasure agent combined with naltrexone to rescue fentanyl-induced ventilatory depression.

Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression.

While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (2), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a Tmax of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl.

Nicotine use disorder and Neuregulin 3: Opportunities for precision medicine.

Nicotine use disorder remains a major public health emergency despite years of trumpeting the consequences of smoking. This is likely due to the complex interplay of genetics and nicotine exposure across the lifespan of these individuals. Genetics influence all aspects of life, including complex disorders such as nicotine use disorder. This review first highlights the critical neurocircuitry underlying nicotine dependence and withdrawal, and then describes the cellular signaling mechanisms involved. Finally, current genetic, genomic, and transcriptomic evidence for new drug development of smoking cessation aids is discussed, with a focus on the Neuregulin 3 Signaling Pathway.

Figure it out on your own: a mixed-method study on pelvic health survivorship care after gynecologic cancer treatments.

PURPOSE: Pelvic health issues after treatment for gynecological cancer are common. Due to challenges in accessing physiotherapy services, exploring virtual pelvic healthcare is essential. This study aims to understand needs, preferences, barriers, and facilitators for a virtual pelvic healthcare program for gynecological cancer survivors. METHODS: A multi-center, sequential mixed-methods study was conducted. An anonymous online survey (N=50) gathered quantitative data on pelvic health knowledge, opportunities, and motivation. Focus groups (N=14) explored patient experiences and consensus on pelvic health interventions and virtual delivery. Quantitative data used descriptive statistics, and focus group analyses employed inductive thematic analysis. Findings were mapped to the capability, opportunity, and motivation (COM-B) behavior change model. RESULTS: Participants reported lacking knowledge about pelvic health interventions and capability related to the use of vaginal dilators and continence care. Barriers to opportunity included lack of healthcare provider-initiated pelvic health discussions, limited time in clinic with healthcare providers, finding reliable information, and cost of physical therapy pelvic health services. Virtual delivery was seen favorably and may help to address motivational barriers related to embarrassment and frustration with care. CONCLUSION: Awareness of pelvic healthcare is lacking among people treated for gynecological cancer. Virtual delivery of pelvic health interventions is perceived as a solution to enhance access while minimizing travel, cost, embarrassment, and exposure risks. IMPLICATIONS FOR CANCER SURVIVORS: A better understanding of the pelvic health needs of individuals following gynecological cancer treatments enables the development of tailored virtual pelvic health rehabilitation interventions which may improve access to pelvic health survivorship care.

The Role of Microglia in Sex- and Region-Specific Blood-Brain Barrier Integrity During Nicotine Withdrawal.

Background: Smoking is the largest preventable cause of death and disease in the United States, with <5% of quit attempts being successful. Microglia activation and proinflammatory neuroimmune signaling in reward neurocircuitry are implicated in nicotine withdrawal symptomology. Microglia are integral regulators of blood-brain barrier (BBB) functionality as well; however, whether the effects of nicotine withdrawal on microglia function impact BBB integrity is unknown. Methods: Mice were treated with chronic nicotine (12 mg/kg/day) and subjected to 48 hours nicotine withdrawal. Regional BBB permeability, together with messenger RNA and protein expression of tight junction proteins, were assessed. PLX5622 chow was used to deplete microglia to evaluate the role of microglia in regulating BBB integrity and nicotine withdrawal symptomology. Results: Female mice had higher baseline BBB permeability in the prefrontal cortex and hippocampus than males. Nicotine withdrawal further exacerbated the BBB permeability selectively in the prefrontal cortex of females. These effects were concurrent with prefrontal cortex alterations in a subset of tight junction proteins with increased proinflammatory responses following nicotine withdrawal in females. Depletion of microglia via PLX5622 treatment prevented all these molecular effects and attenuated withdrawal-induced anxiety-like behavior in female mice. Conclusions: These results are the first to show sex differences in regional BBB permeability during nicotine withdrawal. This represents a possible link to both the reduced smoking cessation success seen in women and women's increased risk for smoking-related neurovascular disorders. Furthermore, these findings open an avenue for sex-specific therapeutics that target microglia and BBB dysfunction during nicotine withdrawal in women.

Dynamic effects of ventral hippocampal NRG3/ERBB4 signaling on nicotine withdrawal-induced responses.

Tobacco smoking remains a leading cause of preventable death in the United States, with approximately a 5% success rate for smokers attempting to quit. High relapse rates have been linked to several genetic factors, indicating that the mechanistic relationship between genes and drugs of abuse is a valuable avenue for the development of novel smoking cessation therapies. For example, various single nucleotide polymorphisms (SNPs) in the gene for neuregulin 3 (NRG3) and its cognate receptor, the receptor tyrosine-protein kinase erbB-4 (ERBB4), have been linked to nicotine addiction. Our lab has previously shown that ERBB4 plays a role in anxiety-like behavior during nicotine withdrawal (WD); however, the neuronal mechanisms and circuit-specific effects of NRG3-ERBB4 signaling during nicotine and WD are unknown. The present study utilizes genetic, biochemical, and functional approaches to examine the anxiety-related behavioral and functional role of NRG3-ERBB4 signaling, specifically in the ventral hippocampus (VH) of male and female mice. We report that 24hWD from nicotine is associated with altered synaptic expression of VH NRG3 and ERBB4, and genetic disruption of VH ErbB4 leads to an elimination of anxiety-like behaviors induced during 24hWD. Moreover, we observed attenuation of GABAergic transmission as well as alterations in Ca2+-dependent network activity in the ventral CA1 area of VH ErbB4 knock-down mice during 24hWD. Our findings further highlight contributions of the NRG3-ERBB4 signaling pathway to anxiety-related behaviors seen during nicotine WD.

Voltage-gated potassium channels control extended access cocaine seeking: a role for nucleus accumbens astrocytes.

Dopaminergic signaling in the nucleus accumbens shell (NAc) regulates neuronal activity relevant to reward-related learning, including cocaine-associated behaviors. Although astrocytes respond to dopamine and cocaine with structural changes, the impact of dopamine and cocaine on astrocyte functional plasticity has not been widely studied. Specifically, behavioral implications of voltage-gated channel activity in the canonically non-excitable astrocytes are not known. We characterized potassium channel function in NAc astrocytes following exposure to exogenous dopamine or cocaine self-administration training under short (2 h/day) and extended (6 h/day) access schedules. Electrophysiological, Ca2+ imaging, mRNA, and mass spectrometry tools were used for molecular characterization. Behavioral effects were examined after NAc-targeted microinjections of channel antagonists and astroglial toxins. Exogenous dopamine increased activity of currents mediated by voltage-gated (Kv7) channels in NAc astrocytes. This was associated with a ~5-fold increase in expression of Kcnq2 transcript level in homogenized NAc micropunches. Matrix-assisted laser desorption/ionization mass spectrometry revealed increased NAc dopamine levels in extended access, relative to short access, rats. Kv7 inhibition selectively increased frequency and amplitude of astrocyte intracellular Ca2+ transients in NAc of extended access rats. Inhibition of Kv7 channels in the NAc attenuated cocaine-seeking in extended access rats only, an effect that was occluded by microinjection of the astrocyte metabolic poison, fluorocitrate. These results suggest that voltage-gated K+ channel signaling in NAc astrocytes is behaviorally relevant, support Kv7-mediated regulation of astrocyte Ca2+ signals, and propose novel mechanisms of neuroglial interactions relevant to drug use.

Increasing access to palliative care for patients with advanced cancer of African and Latin American descent: a patient-oriented community-based study protocol.

BACKGROUND: Cancer disparities are a major public health concern in Canada, affecting racialized communities of Latin American and African descent, among others. This is evident in lower screening rates, lower access to curative, and palliative-intent treatments, higher rates of late cancer diagnoses and lower survival rates than the general Canadian population. We will develop an Access to Palliative Care Strategy informed by health equity and patient-oriented research principles to accelerate care improvements for patients with advanced cancer of African and Latin American descent. METHODS: This is a community-based participatory research study that will take place in two Canadian provinces. Patients and community members representatives have been engaged as partners in the planning and design of the study. We have formed a patient advisory council (PAC) with patient partners to guide the development of the Access to Palliative Care Strategy for people of African and Latin American descent. We will engage100 participants consisting of advanced cancer patients, families, and community members of African and Latin American descent, and health care providers. We will conduct in-depth interviews to delineate participants' experiences of access to palliative care. We will explore the intersections of race, gender, socioeconomic status, language barriers, and other social categorizations to elucidate their role in diverse access experiences. These findings will inform the development of an action plan to increase access to palliative care that is tailored to our study population. We will then organize conversation series to examine together with community partners and healthcare providers the appropriateness, effectiveness, risks, requirements, and convenience of the strategy. At the end of the study, we will hold knowledge exchange gatherings to share findings with the community. DISCUSSION: This study will improve our understanding of how patients with advanced cancer from racialized communities in Canada access palliative care. Elements to address gaps in access to palliative care and reduce inequities in these communities will be identified. Based on the study findings a strategy to increase access to palliative care for this population will be developed. This study will inform ways to improve access to palliative care for racialized communities in other parts of Canada and globally.

Common Misspellings and Their Impact on Health Sciences Literature Search Results.

This study examines the frequency of misspellings in health sciences literature and explores how they affect citation retrieval in multiple databases. Searches for commonly misspelled medical words were conducted in PubMed, CINAHL Complete, APA PsycArticles (ProQuest), APA PsycInfo, and ProQuest Psychology databases. Citations that would be retrieved using a word's correct spelling were removed from the search results. Remaining results were citations that could only be retrieved if the word was misspelled in the search. Articles with clinical significance were targeted. The top five most commonly misspelled words were occurrence, ophthalmology, pruritus, sagittal, and resistance. Ophthalmology had the highest number of citations that contained at least one misspelling, with 57% of those citations "missing" when searched with the correct spelling of the word. The word with the highest percentage (82%) of missed citations was arrhythmia. The results of this study indicate that misspellings in scholarly literature are more prevalent than searchers might realize. The ability to retrieve citations is adversely affected by misspellings, which has the potential to affect patient care. Many opportunities exist in the editorial process to identify and correct misspellings before publication. This is less so once a journal is published. The implications for database searching and manuscript evaluation are discussed.

Preferences, barriers and facilitators regarding virtual pelvic healthcare in individuals with gynaecological cancers: protocol for a patient-oriented, mixed-methods study.

INTRODUCTION: Vaginal pain during intercourse and urinary incontinence are common complaints after gynaecological cancer treatments. Pelvic health physiotherapy treatments aim at optimising function through education on the use of vaginal moisturisers, dilation therapy programme and pelvic floor muscle training. Given that barriers such as time, travel, and costs are known to limit access to physiotherapy services, a virtual pelvic health physiotherapy programme may help to facilitate access. The primary objective of this study is to identify preferences, barriers and facilitators from individuals with gynaecological cancer regarding virtual pelvic healthcare survivorship care. METHODS AND ANALYSIS: This patient-oriented, mixed-methods study will involve an online cross-sectional survey data (phase I) and qualitative data from a series of virtual focus groups (phase II). PHASE I: an anonymous survey will be used to assess the demographics, health status, prevalence of urogenital symptoms, as well as knowledge, barriers and facilitators to pelvic health services of people with gynaecological cancer. A total of N=50 participants from Canada will be recruited through convenience and self-selection sampling. PHASE II: a series of virtual semi-structured focus groups will be conducted with 10-15 participants on key topics related to virtual pelvic healthcare. Interviews will be audio-recorded and transcribed, from which key themes and quotes will be identified. An interpretive description qualitative method will guide analysis and implementation of results. ETHICS AND DISSEMINATION: Approval from the Health Research Ethics Board of Alberta-Cancer Committee (HREBA.CC-21-0498) and of the CISSS Bas-Saint-Laurent (CISSSBSL-2021-10) have been obtained. Informed, electronically signed consent will be required from all participants. Results from this work will be published in a peer-reviewed journal and will be used to inform the development and implementation of a new Pelvic eHealth Module for individuals treated for gynaecological cancers. This module will be incorporated into a comprehensive educational and exercise programme offered by a web-based application.

Dynamic Effects of Ventral Hippocampal NRG3/ERBB4 Signaling on Nicotine Withdrawal-Induced Responses.

Tobacco smoking remains a leading cause of preventable death in the United States, with a less than 5% success rate for smokers attempting to quit. High relapse rates have been linked to several genetic factors, indicating that the mechanistic relationship between genes and drugs of abuse is a valuable avenue for the development of novel smoking cessation therapies. For example, various single nucleotide polymorphisms (SNPs) in the gene for neuregulin 3 (NRG3) and its cognate receptor, the receptor tyrosine-protein kinase erbB-4 (ERBB4), have been linked to nicotine addiction. Our lab has previously shown that ERBB4 plays a role in anxiety-like behavior during nicotine withdrawal (WD); however, the neuronal mechanisms and circuit-specific effects of NRG3-ERBB4 signaling during nicotine and WD are unknown. The present study utilizes genetic, biochemical, and functional approaches to examine the anxiety-related behavioral and functional role of NRG3-ERBB4 signaling, specifically in the ventral hippocampus (VH). We report that 24hWD from nicotine is associated with altered synaptic expression of VH NRG3 and ERBB4, and genetic disruption of VH ErbB4 leads to an elimination of anxiety-like behaviors induced during 24hWD. Moreover, we observed attenuation of GABAergic transmission as well as alterations in Ca2+-dependent network activity in the ventral CA1 area of VH ErbB4 knock-down mice during 24hWD. Our findings further highlight contributions of the NRG3-ERBB4 signaling pathway to anxiety-related behaviors seen during nicotine WD.

Age-specific impacts of nicotine and withdrawal on hippocampal neuregulin signalling.

Smoking remains the leading cause of preventable death in the United States, with 87% of smokers starting before the age of 18. Age of initiation is a major predictive factor for smoking frequency and successful smoking cessation. People who initiate smoking during adolescences are 2.33 times more likely to become heavy smokers and half as likely to quit compared with smokers who started during adulthood. Additionally, schizophrenia, a disease state linked to altered neurodevelopment during adolescence, is a major predictive factor for smoking status. Smoking rates among people suffering from schizophrenia are between 60% and 90%. Interestingly, the Neuregulin Signalling Pathway (NSP), which plays an important role in neurodevelopment, is implicated in both schizophrenia and nicotine use disorder. Specifically, SNPS in neuregulin 3 (Nrg3) and Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4) have been associated with smoking cessation outcomes and schizophrenia. Here, we examine the effects of chronic nicotine (18 mg/kg/day) and 24-h withdrawal on NSP gene expression in the hippocampus of adult (20-week-old) and adolescent (4-week-old) mice. We show that withdrawal from chronic nicotine decreased the expression of Erbb4 mRNA in the hippocampus of the adult mice but increased the expression of cytosolic Erbb4 protein in adolescent mice. Nrg3 mRNA and protein expression was not altered by chronic nicotine or withdrawal in the adult or adolescent cohorts, but Nrg3 mRNA and synaptosomal protein expression was lower in the adult withdrawal group when compared with their adolescent counterparts. These results highlight the age-specific effects of nicotine withdrawal on the NSP and may contribute to the lower quit rate and higher cigarette consumption of smokers who initiation during adolescences.

Strengthening DNP Business Acumen: An Educational Intervention.

BACKGROUND: As reflected in the literature, business acumen for Doctor of Nursing Practice (DNP) students is lacking. Foundational business concepts and applications in the curriculum necessitate the understanding of core business requirements in health care applicable toward DNP leadership roles. METHOD: Course pedagogy used evidence-based materials as well as activities that included the development of business innovation proposals, stakeholder presentations, and business plans, as well as practicum hours. RESULTS: Successful course delivery increased DNP students' knowledge and skills related to business acumen. In addition, students fully grasped the need to sustain and have fully developed scholarly projects that consider the clinical and financial aspects of health care. CONCLUSION: Development of a business course strengthens the needed skills and acumen toward quality and financial performance critical in the DNP leadership role as well as in contributing toward institutions' growth. [J Nurs Educ. 2021;61(4):201-204.].

Nicotine and opioid co-dependence: Findings from bench research to clinical trials.

Concomitant use of tobacco and opioids represents a growing public health concern. In fact, the mortality rate due to smoking-related illness approaches 50% among SUD patients. Cumulative evidence demonstrates that the vulnerability to drugs of abuse is influenced by behavioral, environmental, and genetic factors. This review explores the contribution of genetics and neural mechanisms influencing nicotine and opioid reward, respiration, and antinociception, emphasizing the interaction of cholinergic and opioid receptor systems. Despite the substantial evidence demonstrating nicotine-opioid interactions within the brain and on behavior, the currently available pharmacotherapies targeting these systems have shown limited efficacy for smoking cessation on opioid-maintained smokers. Thus, further studies designed to identify novel targets modulating both nicotinic and opioid receptor systems may lead to more efficacious approaches for co-morbid nicotine dependence and opioid use disorder.

Dealing with Anxious Patients: An Integrative Review of the Literature on Nonpharmaceutical Interventions to Reduce Anxiety in Patients Undergoing Medical or Dental Procedures.

Objectives: A previous systematic literature review (SLR) evaluated 501 experiments on reducing patient anxiety across medical and dental environments. This integrative review examines those interventions and explores possible mechanisms leading to relative success or failure within those environments, in the interest of interprofessional education and communication. Methods: Reviewers evaluated 501 experiments testing interventions for reducing patient anxiety in a variety of medical and dental health care settings. Methodology for the SLR, largely following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, is briefly reviewed. Results: A total of 501 experiments (from 408 articles) met review criteria. One hundred and forty-three Music experiments were included, and Music interventions were largely effective, except in the case of colonoscopy. Education is the only intervention that occasionally (5 times of 130 experiments) raised patient anxiety in the face of a procedure; the discussion focuses on the wisdom of assessing patient need for information. Thirty-seven Cognitive Behavioral Therapy (CBT) experiments of various types are included, with a success rate of 89%, with a particularly high rate of success (12 of 12 experiments) in dentistry. Massage has a success rate that is similar to that of CBT, but Massage has been tested in far fewer specialty areas. Relaxation has been tested in every specialty area, except mechanical ventilation, with promising results. Acupuncture and Acupressure have not been widely tested, but their effectiveness rate is 100% when it comes to reducing patient anxiety in various procedural settings. Similarly, experiments show Hypnosis to be successful in 90% of trials. In contrast, Distraction was successful in only 40% of the experiments summarized, although it was more effective in dentistry. A variety of Nature-based Interventions (Aromatherapy, Nature Sounds, and Visual Stimuli) were highly successful across a variety of settings. Discussion: Possible mechanisms are discussed, along with commentary on feasibility. Limitations include publication bias, small sample sizes, and the lack of placebo controls. Future areas of research are pointed out.

Dealing with Anxious Patients: A Systematic Review of the Literature on Nonpharmaceutical Interventions to Reduce Anxiety in Patients Undergoing Medical or Dental Procedures.

Objectives: State (situational) anxiety can create suboptimal outcomes for patients across a variety of health care specializations. While anxiolytic medications reduce anxiety, problematic side effects can compromise outcomes. These challenges have spurred searches for nonpharmaceutical approaches to alleviate patient anxiety. This systematic literature review, largely following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, aimed to determine patterns and effectiveness of interventions across medical health care specialty areas, including dentistry. Methods: A systematic review was conducted, using PubMed, CINAHL, and PsycINFO databases, with search terms related to anxiety, specific interventions, and medical or dental procedures. Hand searching for additional citations was performed on the bibliographies of dissertations, meta-analyses, and systematic reviews that met article inclusion criteria. The search process yielded 48,324 articles and 257 dissertations published in English between 1974 and 2018. Each abstract was evaluated for inclusion by two reviewers, yielding 718 articles that were read and evaluated for outcomes, risk of bias, pretest and post-test, controls and quality, using a Critical Appraisal Skills Programme instrument. Of these, 408 articles, describing 501 experimental trials, were accepted for inclusion in this analysis. Results: A total of 50,343 patients were included in these experiments, with an overall success rate of 71% for reducing patient anxiety. Results are summarized by health care specialty area: surgery, oncology, cardiology, obstetrics/gynecology, dentistry, and pain/trauma, and the following diagnostic testing and intervention areas: imaging, colonoscopy, mechanical ventilation, and other. The largest number of experiments (114) was in the surgery category. The types of interventions included music, education, relaxation, cognitive behavioral therapy (CBT), massage, distraction, hypnosis, acupuncture/acupressure, social support, aromatherapy, nature sounds, natural visual stimuli, special garment, and other. The largest numbers of experiments were done with music (143) and education (130). Discussion: The following interventions were most successful, reducing anxiety in over 70% of experiments: music, CBT, relaxation, massage, acupuncture/acupressure, hypnosis, and natural sounds. Confidence in results is limited by publication bias, small sample sizes, and the lack of placebo controls. Directions for future research are discussed.