Effects of Antiretroviral Treatment on Central and Peripheral Immune Response in Mice with EcoHIV Infection.

HIV infection is an ongoing global health issue, despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter the immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify the effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F), and tenofovir alafenamide (TAF) on the expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In the absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.

Effects of antiretroviral treatment on central and peripheral immune response in mice with EcoHIV infection.

HIV infection is an ongoing global health issue despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F) and tenofovir alafenamide (TAF) on expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation.

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between HIV infection and cocaine use disorder is likely bidirectional, with cocaine use directly impacting immune function while HIV infection alters addiction-related behavior. To better characterize the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilizes a humanized mouse model to investigate the outcomes of HIV-1 infection on cocaine-related behaviors in a conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection selectively impairs cocaine CPP extinction without effecting reinstatement or cocaine seeking under conflict. Behavioral alterations are accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes are observed in human cytokines, including HIV-induced reductions in human TNFα, and cocaine and HIV interactions on GM-CSF levels. Together these data provide new insights into the unique neurobehavioral outcomes of HIV infection and cocaine exposure and how they interact to effect immune responses.

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation.

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between HIV infection and cocaine use disorder is likely bidirectional, with cocaine use directly impacting immune function while HIV infection alters addiction-related behavior. To better characterize the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilized a humanized mouse model to investigate the outcomes of HIV-1 infection on cocaine-related behaviors in a conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection selectively impaired cocaine CPP extinction without effecting reinstatement or cocaine seeking under conflict were observed. Behavioral alterations were accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes were observed in both mouse and human cytokines, including HIV-induced reductions in mouse IL-1α and G-CSF and human TNFα, and cocaine induced alterations in mouse GM-CSF. Together these data provide new insights into the unique neurobehavioral outcomes of HIV infection and cocaine exposure and how they interact to effect immune responses.

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation.

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between progressive HIV infection and cocaine use disorder is likely bidirectional, with cocaine use having direct effects on immune function while HIV infection can alter addiction-related behavior. To better characterized the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilized a humanized mouse model to investigate the outcomes of progressive HIV infection on cocaine-related behaviors in a cocaine conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection did not impact the formation of a cocaine CPP, but did result in resistance to extinction of the CPP. No effects of HIV on yohimbine-primed reinstatement or cocaine seeking under conflict were observed. These behavioral alterations were accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes were observed in both mouse and human markers. Among other targets, this included HIV-induced reductions in mouse IL-1α and G-CSF and human TNFα and cocaine-induced alterations in human TNFα and mouse GM-CSF such that cocaine exposure increases both cytokines only in the absence of HIV infection. Together these data provide new insights into the unique neurobehavioral processes underlying HIV infection and cocaine use disorders, and further how they interact to effect immune responses.

Effects of adolescent ethanol exposure on adult nondrug reward seeking behavior in male and female mice.

BACKGROUND: Adolescent alcohol use is associated with an increased likelihood of developing an alcohol use disorder in adulthood, potentially due to the effects of alcohol exposure on reward-seeking behavior. However, it remains unclear whether adolescent drinking is sufficient to alter nondrug reward seeking in adulthood. As adolescence is a period of both brain and sexual maturation, which occur in a sex-dependent manner, males and females may be differentially sensitive to the consequences of adolescent alcohol exposure. The present study investigated whether adolescent ethanol exposure affected food reward taking and seeking in male and female adult mice. METHODS: Male and female C57BL/6J mice underwent intermittent ethanol exposure (AIE) via vapor inhalation during early adolescence (28-42 days of age). At 10 weeks of age, the mice were trained in a conditioned place preference paradigm (CPP) for a food reward. We measured food consumption, CPP, and cFos expression in multiple brain regions following CPP testing. Data were analyzed using repeated measures analysis of variance with exposure (air vs. AIE), sex, and time as factors. RESULTS: AIE exposure increased food consumption during CPP training in adult male mice, but reduced pellet consumption in adult female mice. AIE exposure impaired CPP expression only in female mice. Despite these behavioral differences, exposure to the reward-paired chamber did not induce differential cFos expression following CPP testing in the prelimbic and infralimbic cortices or the nucleus accumbens core and shell. CONCLUSION: These findings indicate that adolescent ethanol exposure disrupted nondrug reward taking and seeking in adulthood in female mice and altered consumption in adult male mice.

A History of Low-Dose Ethanol Shifts the Role of Ventral Hippocampus during Reward Seeking in Male Mice.

Although casual drinkers are a majority of the alcohol drinking population, understanding of the long-term effects of chronic exposure to lower levels of alcohol is limited. Chronic exposure to lower doses of ethanol may facilitate the development of alcohol use disorders, potentially because of ethanol effects on reward learning and motivation. Indeed, our previously published findings showed that chronic low-dose ethanol exposure enhanced motivation for sucrose in male, but not female, mice. As the ventral hippocampus (vHPC) is sensitive to disruption by higher doses of chronic ethanol and tracks reward-related information, we hypothesized that this region is impacted by low-dose ethanol and, further, that manipulating vHPC activity would alter reward motivation. In vivo electrophysiological recordings of vHPC population neural activity during progressive ratio testing revealed that vHPC activity was suppressed in the period immediately after reward seeking (lever press) in ethanol-naive controls, whereas suppression of vHPC activity anticipated reward seeking in ethanol-exposed mice. In both ethanol-naive and exposed mice, vHPC activity was suppressed before a reward magazine entry. Temporally selective inhibition of vHPC using optogenetics increased motivation for sucrose in ethanol-naive controls, but not in ethanol-exposed mice. Further, regardless of exposure history, vHPC inhibition promoted checking of the reward magazine, indicating a role for vHPC in reward tracking. There was no effect of chemogenetic inhibition of the vHPC either during training or testing on sucrose reward motivation. These results reveal novel ethanol-induced alterations in vHPC neural activity that shift how vHPC activity is able to regulate reward seeking.

Developing an interprofessional team to support patients prescribed long-term high-dose opioid therapy.

Despite decreases in US opioid prescribing rates, daily morphine milligram equivalents (MME) prescribed per person remains three times higher than in 1999. An interprofessional team (IPT) was developed to support pain management for patients prescribed long-term high-dose opioids (HDO) in a Federally Qualified Health Center. The IPT utilized a clinical pharmacist, addiction nurse, medical director, and another physician or nurse practitioner to manage adults prescribed long-term HDO, defined as exceeding 50 daily MME. Visits focused on patient education including risks associated with long-term HDO use and effective pain management. The IPT engaged in supportive, individualized care planning for safer, evidence-based pain management, which included, but was not limited to opioid tapers, adjuvant non-opioid pain medications (NOPM), non-pharmacological therapy (NPT), and naloxone co-prescribing. The IPT saw 90% (n = 19) of eligible patients. Excluding outliers, the cohort demonstrated an average 18% ± 24.9 decrease in daily MME. The most common NOPM were acetaminophen, NSAIDs, and pregabalin, and the most common NPT were physical, aquatic, and behavioral therapy. Shared decision-making, collaborative teamwork, and simple patient-centered goals are key to moving patients toward safer, evidence-based therapy.

Estrous cycle and hormone regulation of stress-induced reinstatement of reward seeking in female mice.

Women are more vulnerable to stress-induced craving, which may be associated with increased vulnerability to relapse. Susceptibility to stress-induced craving also appears to be modulated by the menstrual cycle and is negatively correlated with circulating progesterone levels in women. However, the factors that contribute to relapse vulnerability are poorly characterized in female animals. In this study, we assessed whether chronic ethanol exposure, estrous cycle, or exogenous progesterone administration modulated vulnerability to stress-induced reinstatement. To model ethanol dependence, adult female C57Bl/6J mice underwent chronic intermittent ethanol (CIE) exposure via vapor inhalation. Seventy-two hours after the final ethanol exposure, food-restricted mice began training in a conditioned place preference paradigm (CPP) for a food reward, followed by extinction training. Mice were then subjected to forced swim stress and assessed for reinstatement of their preference for the reward-paired chamber. CIE did not affect stress-induced reinstatement. However, stress-induced reinstatement was attenuated during the diestrus phase, when endogenous levels of progesterone peak in female mice. Further, administration of exogenous progesterone mimicked the attenuated reinstatement observed in diestrus. These findings indicate that circulating hormone levels modulate susceptibility to relapse-like behaviors and implicate progesterone as a potential target for treating stress-induced relapse in women.

Update on the diagnosis and management of pediatric laryngotracheal stenosis.

INTRODUCTION: Laryngotracheal stenosis comprises a broad spectrum of congenital and acquired conditions that commonly cause pediatric airway obstruction. With the introduction and popularization of operative procedures such as laryngotracheoplasty, cricotracheal resection, and slide tracheoplasty more patients are presenting with airway issues at multiple anatomic levels. A combination of endoscopic and open techniques continues to be utilized for these complex issues. Additionally, there are specific long-term considerations for the post reconstruction patient. AREAS COVERED: This review highlights important aspects of the diagnosis, work up, and surgical treatment of pediatric laryngotracheal stenosis with updates for revision airway surgery and the post reconstruction patient. Important research articles and techniques within pediatric airway reconstruction are summarized and included in the review, in addition to recent articles from the last five years on pediatric laryngotracheal stenosis which were identified through a search of the PubMed database. EXPERT OPINION: The multidisciplinary concept of evaluation and treatment of laryngotracheal stenosis continues to be essential. Revision airway surgery presents unique challenges to improve the quality of life of patients as they age after reconstruction. Tracheal transplantation remains an important research area in the treatment of laryngotracheal stenosis.

Laryngotracheal separation through the cricoid ring for management of tracheobronchomegaly.

Tracheobronchomegaly is a rare condition characterized by diffuse dilation of the trachea and main bronchi. In ventilator-dependent neonates with tracheobronchomegaly, a tracheostomy may be hazardous due to the lack of an appropriate tracheostomy tube size that can fit the enlarged trachea. Here, we describe a modification of the laryngotracheal separation procedure to permit ventilation in a child with tracheobronchomegaly and severe bronchopulmonary dysplasia.

The Impact of Embodiment and Avatar Sizing on Personal Space in Immersive Virtual Environments.

In this paper, we examine how embodiment and manipulation of a self-avatar's dimensions - specifically the arm length - affect users' judgments of the personal space around them in an immersive virtual environment. In the real world, personal space is the immediate space around the body in which physical interactions are possible. Personal space is increasingly studied in virtual environments because of its importance to social interactions. Here, we specifically look at two components of personal space, interpersonal and peripersonal space, and how they are affected by embodiment and the sizing of a self-avatar. We manipulated embodiment, hypothesizing that higher levels of embodiment will result in larger measures of interpersonal space and smaller measures of peripersonal space. Likewise, we manipulated the arm length of a self-avatar, hypothesizing that while interpersonal space would change with changing arm length, peripersonal space would not. We found that the representation of both interpersonal and peripersonal space change when the user experiences differing levels of embodiment in accordance with our hypotheses, and that only interpersonal space was sensitive to changes in the dimensions of a self-avatar's arms. These findings provide increased understanding of the role of embodiment and self-avatars in the regulation of personal space, and provide foundations for improved design of social interaction in virtual environments.

Altered Peripersonal Space and the Bodily Self in Schizophrenia: A Virtual Reality Study.

Self-disturbances such as an anomalous perception of one's own body boundary are central to the phenomenology of schizophrenia (SZ), but measuring the spatial parameters of the hypothesized self-other boundary has proved to be challenging. Peripersonal space (PPS) refers to the immediate zone surrounding the body where the self interacts physically with the environment; the space that corresponds to hypothesized self-other boundary. PPS is represented by enhanced multisensory integration and faster reaction time (RT) for objects near the body. Thus, multisensory RT tasks can be used to estimate self-other boundary. We aimed to quantify PPS in SZ using an immersive virtual reality visuotactile RT paradigm. Twenty-four participants with SZ and 24 demographically matched controls (CO) were asked to detect tactile vibration while watching a ball approaching them, thrown by either a machine (nonsocial condition) or an avatar (social condition). Parameters of PPS were estimated from the midpoint of the spatial range where the tactile RT decreased most rapidly (size) and the gradient of the RT change at this midpoint (slope). Overall, PPS was smaller in participants with SZ compared with CO. PPS slope for participants with SZ was shallower than CO in the social but not in nonsocial condition, indicating an increased uncertainty of self-other boundary across an extended zone in SZ. Social condition also increased false alarms for tactile detection in SZ. Clinical symptoms were not clearly associated with PPS parameters. These findings suggest the context-dependent nature of weakened body boundary in SZ and underscore the importance of reconciliating objective and subjective aspects of self-disturbances.

Effect of Graft Size on Air-bone Gap Closure in Cartilage Button Tympanoplasty.

OBJECTIVE: To study the effect of graft size on postoperative air-bone gap in children undergoing butterfly inlay cartilage tympanoplasty using circular punch grafts. STUDY DESIGN: Retrospective case review. SETTING: Tertiary, academic children's hospital. PATIENTS: Children less than 16 years old undergoing circular butterfly inlay tympanoplasty using 4, 5, or 6 mm round grafts. INTERVENTION: Butterfly inlay tympanoplasty using circular punch graft harvest technique. MAIN OUTCOME MEASURES: Postoperative pure-tone average and air-bone gap. RESULTS: Fifty-two children were included in the analysis: 18 in the 4 mm group, 28 in the 5 mm group, and 6 in the 6 mm group. There was no significant difference in either postoperative pure-tone average or air-bone gap among the three groups. Closure rates for the 4, 5, and 6 mm graft groups were 94, 96, and 67%, respectively, for an overall rate of 92%. CONCLUSIONS: Cartilage button butterfly inlay tympanoplasty with punch graft is an effective method for tympanic membrane repair with similar hearing results among various graft diameters but may have diminished success with perforations requiring grafts larger than 5 mm. Larger case series are necessary to determine if larger defects are best managed with other repair techniques.

Pediatric orbital floor fractures and the oculocardiac reflex: Experience from a level I trauma center.

PURPOSE: The purpose of this study is to determine whether bradycardia associated with the oculocardiac reflex is a significant source of morbidity in the post injury period following orbital floor fractures in children. MATERIALS/METHODS: A retrospective review of all pediatric patients who presented to our emergency department with an orbital floor fracture from May 1, 2016 to June 1, 2018 were included. Basic demographic data was collected as well as mechanism of injury, presence of bradycardia, and time to operating room. Morbidity was based on the need for medications to treat bradycardia. RESULTS: Thirty-five pediatric patients with orbital floor fractures were reviewed. 6 (17.1%) patients had post injury bradycardia, with one patient requiring medication to stabilize their heart rate. There was no statistically significant difference in sex, race/ethnicity, or age in patients with or without bradycardia (p > 0.05) however there was a significant relationship between bradycardia and need for operative repair (X2 = 7.88, df = 1, p = 0.005). The most common mechanism of injury was motor vehicle collision (45.7%). The average time to the operating room was 145 h (6.04 days). CONCLUSIONS: While activation of the oculocardiac reflex is a legitimate concern in the post injury period, there is unlikely to be significant morbidity due to bradycardia, and the greater concern should be for the ischemic muscle injury incurred from the fracture.