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Clinical evidence has linked increased peripheral pro-inflammatory cytokines with post-traumatic stress disorder (PTSD) symptoms. However, whether inflammation contributes to or is a consequence of PTSD is still unclear. Previous research shows that stress can activate purinergic P2X7 receptors (P2X7Rs) on microglia to induce inflammation and behavioral changes. In this investigation, we examined whether P2X7Rs contribute to the development of PTSD-like behaviors induced by single prolonged stress (SPS) exposure in rats. Consistent with the literature, exposing adult male and female rats to SPS produced a PTSD-like phenotype of impaired fear extinction and extinction of cue-induced center avoidance one week after exposure. Next, we examined if inflammation precedes the behavioral manifestations. Three days after SPS exposure, increased inflammatory cytokines were found in the blood and hippocampal microglia showed increased expression of the P2X7R, IL-1β, and TNF-α, suggesting increased peripheral and central inflammation before the onset of impaired fear extinction. In addition, SPS-exposed animals with impaired fear extinction recall also had more Iba1-positive microglia expressing the P2X7R in the ventral hippocampus. To determine whether P2X7Rs contribute to the PTSD-related behaviors induced by SPS exposure, we gave ICV infusions of the P2X7R antagonist, A-438079, for one week starting the day of SPS exposure. Blocking P2X7Rs prevented the SPS-induced impaired fear extinction and extinction of cue-induced center avoidance in male and female rats, suggesting that SPS activates P2X7Rs which increase inflammation to produce a PTSD-like phenotype., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Single prolonged stress (SPS) is a preclinical rodent model for studying post-traumatic stress disorder (PTSD)-like behaviors. Previously we found that increased expression of the microglial marker Iba-1 in the ventral hippocampus after SPS exposure was associated with impaired fear extinction, suggesting that microglial activity contributed to the SPS-induced behavioral changes. To test this, we examined whether reducing microglia with the colony-stimulating factor 1 receptor blocker, PLX3397, in the diet would prevent the SPS-induced extinction impairment. Male rats exposed to SPS showed enhanced fear acquisition and impaired fear extinction memory. Adding PLX3397 to the diet prevented these behavioral changes. In contrast, PLX3397 did not prevent SPS from impairing fear extinction memory in the female rats. Despite the sex-dependent behavioral effects, we found a reduced number and area fraction of Iba-1+ microglia in both male and female rats suggesting that PLX3397 had similar effects on microglia in both sexes. Altogether, these results suggest that microglia contribute to the behavioral changes induced by SPS in male but not female rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Torres-Rodriguez, Ortiz-Nazario, Rivera-Escobales, Velazquez, Colón and Porter.)

Receiving a diagnosis of depression can have an important impact on the lives of adolescents. However, there is limited information about how youth tackle, attribute meaning to and understand mental health diagnoses. The aim of this study was to explore adolescents' initial reactions after receiving a clinical diagnosis of Major Depressive Disorder in the context of a neurobiological study of depression in Brazil. Using a qualitative design, eight Brazilian adolescents were interviewed twice: immediately after a psychiatric assessment and neuroimaging study, in which they were given a diagnosis of depression, and in a follow-up visit 2 weeks later. Interviews were designed to explore the subjective experience of receiving the diagnosis and the impacts of depression on adolescents' lives. Framework Analysis was used to analyze the accounts. Diagnosis was perceived as a reification of an abnormal status, highlighting the role of stigma and the process of disclosing the diagnosis to others. Adolescents reported the multiple sensemaking processes that occurred when they received a diagnosis of depression, and most struggled with the idea that negative emotions would equate their experience with a disorder. The results show that future efforts could enhance clinical assessment processes with adolescents by exploring adolescents' reactions to diagnosis, as well as the support networks available to them, resulting in increased help-seeking behaviors, and diminished social and personal stigma.

Objective: To explore associations between self-reported weekly physical activity and depressive symptomatology among adolescents in a school-based sample from Brazil., Methods: We surveyed 7,405 adolescents aged 14 to 16 years in 101 public schools in Porto Alegre, Brazil. We assessed physical activity using an adapted version of the Patient-Centered Assessment and Counseling for Exercise Plus Nutrition - Adolescent Physical Activity Measure (PACE+), and depressive symptoms using the Brazilian Portuguese version of the Patient Health Questionnaire - Adolescent Version. We compared the depressive symptom scores among adolescents with varying levels of physical activity., Results: Of the overall sample, 84.4% exercised less than the recommended frequency of 60 minutes/day, at least 5 days/week, of moderate to intense physical activity (PACE+ score ≥ 5). Adolescents whose physical activity levels fell below that threshold had higher median depression scores (8 [IQR = 10] vs. 7 [IQR = 9], W = 4060461, p < 0.001). A similar pattern was observed for depression scores in those with PACE+ < 1 (median of 10 [IQR = 11]) and ≥ 1 (7 [IQR = 9], W = 7457608, p < 0.001)., Conclusion: In this large sample of Brazilian adolescents, those who exercised less frequently and vigorously than their peers reported more depressive symptoms.

Background: Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center., Methods: We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care., Results: Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool's ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5-6 portal messages., Conclusions: Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice., (© 2021. The Author(s).)

Background: The characterization of adolescents at high risk for developing depression has traditionally relied on the presence or absence of single risk factors. More recently, the use of composite risk scores combining information from multiple variables has gained attention in prognostic research in the field of mental health. We previously developed a sociodemographic composite score to estimate the individual level probability of depression occurrence in adolescence, the Identifying Depression Early in Adolescence Risk Score (IDEA-RS). Objectives: In this report, we present the rationale, methods, and baseline characteristics of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo), a study designed for in-depth examination of multiple neurobiological, psychological, and environmental measures associated with the risk of developing and with the presence of depression in adolescence, with a focus on immune/inflammatory and neuroimaging markers. Methods: Using the IDEA-RS as a tool for risk stratification, we recruited a new sample of adolescents enriched for low (LR) and high (HR) depression risk, as well as a group of adolescents with a currently untreated major depressive episode (MDD). Methods for phenotypic, peripheral biological samples, and neuroimaging assessments are described, as well as baseline clinical characteristics of the IDEA-RiSCo sample. Results: A total of 7,720 adolescents aged 14-16 years were screened in public state schools in Porto Alegre, Brazil. We were able to identify individuals at low and high risk for developing depression in adolescence: in each group, 50 participants (25 boys, 25 girls) were included and successfully completed the detailed phenotypic assessment with ascertainment of risk/MDD status, blood and saliva collections, and magnetic resonance imaging (MRI) scans. Across a variety of measures of psychopathology and exposure to negative events, there was a clear pattern in which either the MDD group or both the HR and the MDD groups exhibited worse indicators in comparison to the LR group. Conclusion: The use of an empirically-derived composite score to stratify risk for developing depression represents a promising strategy to establish a risk-enriched cohort that will contribute to the understanding of the neurobiological correlates of risk and onset of depression in adolescence., Competing Interests: VM has received research funding from Johnson & Johnson, a pharmaceutical company interested in the development of anti-inflammatory strategies for depression, but the research described in this paper is unrelated to this funding. LAR has received grant or research support from, served as a consultant to, and served on the speakers' bureau of Bial, Medice, Novartis/Sandoz, Pfizer, and Shire/Takeda in the last 3 years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him have received unrestricted educational and research support from the following pharmaceutical companies: Novartis/Sandoz, and Shire/Takeda. He has received travel grants from Shire/Takeda to take part in the 2018 American Psychiatric Association congress. He also receives authorship royalties from Oxford Press and ArtMed. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kieling, Buchweitz, Caye, Manfro, Pereira, Viduani, Anés, Battel, Benetti, Fisher, Karmacharya, Kohrt, Martini, Petresco, Piccin, Rocha, Rohde, Rohrsetzer, Souza, Velazquez, Walsh, Yoon, Zajkowska, Zonca, Swartz and Mondelli.)

The factors influencing resiliency to the development of post-traumatic stress disorder (PTSD) remain to be elucidated. Clinical studies associate PTSD with polymorphisms of the FK506 binding protein 5 (FKBP5). However, it is unclear whether changes in FKBP5 expression alone could produce resiliency or susceptibility to PTSD-like symptoms. In this study, we used rats as an animal model to examine whether FKBP5 in the infralimbic (IL) or prelimbic (PL) medial prefrontal cortex regulates fear conditioning or extinction. First, we examined FKBP5 expression in IL and PL during fear conditioning or extinction. In contrast to the stable expression of FKBP5 seen in PL, FKBP5 expression in IL increased after fear conditioning and remained elevated even after extinction suggesting that IL FKBP5 levels may modulate fear conditioning or extinction. Consistent with this possibility, reducing basal FKBP5 expression via local infusion of FKBP5-shRNA into IL reduced fear conditioning. Furthermore, reducing IL FKBP5, after consolidation of the fear memory, enhanced extinction memory indicating that IL FKBP5 opposed formation of the extinction memory. Our findings demonstrate that lowering FKBP5 expression in IL is sufficient to both reduce fear acquisition and enhance extinction, and suggest that lower expression of FKBP5 in the ventral medial prefrontal cortex could contribute to resiliency to PTSD., (© 2017 Criado-Marrero et al.; Published by Cold Spring Harbor Laboratory Press.)

Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: To assess the influence of exposure to tobacco cigarette smoke on the eosinophil count and the frequency of apoptosis of eosinophils in the nasal mucosa of teenagers with perennial allergic rhinitis., Methods: Fifty patients were evaluated (aged 10 to 19 years old): 25 patients with and 25 patients with no recent exposure to tobacco cigarette smoke, by means of The Global Youth Tobacco Survey and cotinine/creatinine ratio. After a clinical evaluation, all the patients replied to a validated questionnaire of the severity of nasal symptoms; then, a nasal sample was processed to identify the eosinophil count and the frequency of apoptosis of eosinophils., Results: Patients with active exposure to tobacco cigarette smoke had higher eosinophil counts than patients with no exposure to the smoke. In the two groups, apoptosis of eosinophils in the nasal mucosa was scarce and no significant correlation was observed between the frequency/severity of the nasal symptoms and the eosinophil count., Conclusion: Teenagers with perennial allergic rhinitis and active exposure to tobacco cigarette smoke may show increased eosinophil counts in the nasal mucosa, which might not be related to apoptosis of eosinophils or to the frequency/severity of nasal symptoms.

The estimated number of out-of-hospital care arrest cases is about 300,000 per year in the United States. Two landmark studies published in 2002 demonstrated that the use of therapeutic hypothermia after cardiac arrest decreased mortality and improved neurologic outcome. Based on these studies, the International Liaison Committee on Resuscitation and the American Heart Association recommended the use of therapeutic hypothermia after cardiac arrest. Therapeutic hypothermia is defined as a controlled lowering of core body temperature to 32 degrees C to 34 degrees C. This temperature goal represents the optimal balance between clinical effect and cardiovascular toxicity. Therapeutic hypothermia does require resources to implement-including device, close nursing care, and monitoring. It is important to select patients who have potential for benefit from this technique which is a limited resource and carries potential complications. A collaborative team approach involving physicians and nurses is critical for successful development and implementation of this kind of a protocol. In 2004, the "Advanced Cardiac Admission Program" was launched at the St. Luke's Roosevelt Hospital Center of Columbia University in New York. The program consists of a series of projects, which have been developed to bridge the gap between published guidelines and implementation during "real world" patient care. In this article, we are reporting our latest project for the comprehensive management of survivors of out-of-hospital cardiac arrest. The pathway is divided into 3 steps: Step I, From the field through the emergency department into the cardiac catherization laboratory and to the critical care unit; Step II, Induced invasive hypothermia protocol in the critical care unit (this step is divided into 3 phases: 1, invasive cooling for the first 24 hours; 2, rewarming; 3, maintenance); Step III, Management post the rewarming phase including the recommendation for out-of-hospital therapy and the ethical decision to define goal of care. We hope that this novel pathway will bridge the gap between the complex guidelines and the actual clinical practice and will improve the survival and neurologic condition of patients suffering cardiac arrest.