Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Cocaine-induced behavioral sensitization is greater in adolescent than in adult mice and heightens cocaine-induced conditioned place preference in adolescents

Adolescents are more sensitive than adults to the neural and behavioral effects of psychostimulants, and exhibit greater vulnerability to drug abuse, dependence or relapse into these conditions. We have reported that cocaine pretreatment during adolescence promotes the expression of behavioral sensitization to a greater extent than when the pretreatment occurs at adulthood. Behavioral sensitization has been associated to the transition from drug use to addiction and is postulated to indicate heightened sensitivity to the appetitive motivational effects of drugs. The relationship between behavioral sensitization and conventional measures of drug reward, such as conditioned place preference (CPP), has yet to be thoroughly investigated, and little is known about age-related differences in this phenomenon. The present study tested cocaine-induced CPP in adolescent and adult mice exposed to cocaine (or vehicle) pretreatment, either in an intermittent or “binge” (i.e., heavy cocaine use on a single occasion, which increases the likelihood of experiencing cocaine-related problems) fashion. Cocaine administration induced behavioral sensitization to a greater extent in adolescent than in adult mice. Cocaine-induced CPP was fairly similar in vehicle pretreated adolescent and adult mice, yet greater in adolescent vs. adults after cocaine-induced sensitization. The results confirmed the higher sensitivity of adolescent mice to cocaine-induced behavioral sensitization and suggest its association with greater sensitivity to cocaine's rewarding effects.Fil: Camarini, Rosana. Universidade do Sao Paulo. Instituto de Ciencias Biomedicas; BrasilFil: Hoffmann, Lucas Barbosa. Universidade do Sao Paulo. Instituto de Ciencias Biomedicas; BrasilFil: Suarez, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Rae, Mariana. Universidade do Sao Paulo. Instituto de Ciencias Biomedicas; BrasilFil: Marcourakis, Tania. Universidade do Sao Paulo. Instituto de Ciencias Biomedicas; BrasilFil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

Perspectives of Jamaican nurses and decision makers on the impact of the HIV/AIDS epidemic on the nursing workforce

Objective: To explore how the HIV and AIDS epidemic has affected the nursing workforce and the provision of HIV/AIDS nursing services in Jamaica. Methods: A purposive sample of 20 frontline nurses, nurse managers and 9 decision makers was drawn from participating health institutions. Qualitative semi-structured interviews were audio taped and transcribed verbatim. A coding framework was developed which guided both descriptive and conceptual analysis. Results: The majority of respondents reported that the HIV/AIDS epidemic created increased challenges to the provision of quality nursing care due to higher patient/nurse ratios, increased workload, emotional and physical burnout, greater risk of occupational injury and HIV infection. All respondents revealed that strict implementation of universal precautions was constrained by inadequate supplies of protective gears and equipment. Most of the respondents described stigma perpetrated by nurses towards individuals living with the disease. Conversely, some respondents reported a reduction in bias towards patients living with HIV/AIDS. Institutional responses to the epidemic included increased training in HIV/AIDS care and more rigorous application of standards and procedures for infection control; created new opportunities for nurse leadership in implementing programs and new job opportunities for nurses in Non Governmental Organizations involved in HIV and AIDS care. Conclusion: Findings of this study suggest largely negative effects of the HIV/AIDS epidemic on the nursing workforce as well as indirect positive outcomes. The negative impact on quality of care exists both on individual and institutional levels. Policies and organizational supports are required to reduce the impact of the HIV/AIDS epidemic on the nursing workforce. Key Words: HIV, AIDS, Nursing Workforce, Decision Makers, Jamaic

Spearheading Simulation in a Middle-Income Country: An International Collaboration

Faculty members in low- and middle-income countries (LMICs) are seeking to develop simulation centers with fewer resources. The aim of this study was to describe an effective approach to build capacity and facilitate the incorporation of simulation into the curriculum of a nursing program in a middle-income country.A team of expert faculty members from the United States visited Jamaica to provide a train-the-trainer simulation workshop.Innovative and engaging strategies were used to foster faculty member development including codevelopment of simulations, implementation of simulation, codebriefing experiences, and curriculum development.Boards of nursing in LMICs are hesitant to accept simulation as the majority of evidence supporting simulation has been conducted in high-income countries. To influence policy, faculty members are urged to conduct more simulation research in LMICs to establish an evidence base. Collaborations of nurse faculty members involving high-, middle-, and low-income countries are recommended to further the science of simulation worldwide.•Faculty in middle- and low-income countries are increasingly seeking to develop their own simulation centers with fewer resources.•As simulation centers begin to proliferate across low- and middle-income countries, therein lies opportunities for international collaborations to improve nursing education.•As a solid body of evidence is lacking, it is critical that simulation research be conducted in low- and middle-income countries to influence policy, improve nursing education, and improve patient outcomes globally.•Collaborations of nurse faculty members from high-income and middle- to low-income countries are recommended to further the science of simulation and facilitate adoption of simulation worldwide

Nurses’ experiences of stigma in HIV and AIDS care in Jamaica

Objective: To explore how multilayered dimensions of stigma influence nurses provision of nursing care to patients and families living with HIV/AIDS. Methods: A cross-sectional survey was done among 201 frontline nurses, midwives and nurse managers working in the public health care system in Westmoreland, St. James, Trelawny, Kingston & St. Andrew, St. Catherine and St. Thomas. Stigma was measured using the validated HIV/AIDS Stigma Instrument for Nurses. Qualitative data were collected in a purposive sample of 20 nurses and midwives using a semi structured interview guide. Interviews were audio taped and transcribed verbatim coded and thematically analyzed. Results: Quantitative data revealed low levels of stigma against patients with HIV/AIDS. Nurses frequently reported occurrences of subtle stigmatization of patients such as making patients with HIV last to be cared for 48 (23.9%), shouting at or scolding patients with HIV/AIDS 46 (22.4%) and generally giving poor quality care 42 (22.8%). A small proportion, 20 (9.7%) of respondents also reported that nurses who care for patients with HIV/AIDS were stigmatized, particularly nurses who work in hospitals rather than health centres Qualitative interviews with nurses and midwives revealed that stigma and discrimination was a major factor that influenced nurses’ ability to provide care for patients living with HIV. Fear of stigma and discrimination also influenced patients’ decision to disclose their HIV status, which in turn influenced nurses’ ability to provide care. Conclusion: Stigma associated with HIV/AIDS hinders nurses from providing the best possible nursing care to patients and demonstrates a need for continuing education. Key Words: Stigma, Nurses; Nursing Care, HIV/AIDS

Building Capacity for Nursing and Midwifery Education Through an Asynchronous Online Course

Global organizations urge toward transformative, lifelong learning for nurses and midwives. Throughout Latin America and the Caribbean, strengthening the quality of nursing and midwifery education is top priority. A regional partnership of World Health Organization Collaborating Centers aimed to develop a user-friendly, culturally relevant, and adaptable educational quality improvement intervention. Following the five-step ADDIE process, experts analyzed objectives and needs, designed activities and assessments, and determined optimum delivery of course content. A self-directed, asynchronous online course was developed, in line with regional needs and mandates. Three sequential online educational modules for English-speaking and Spanish-speaking nurse and midwife educators focused on (a) principles of teaching and learning, (b) instructional strategies, and (c) methods to evaluate students and courses. Content and design were externally reviewed and culturally adapted. Upon completion of pilot testing and evaluation, final course versions in both languages are expected to become freely accessible. [J Nurs Educ. 2020;59(1):38-41.]

Re-enactment Recipes

"Re-enactment Recipes gathers essays, photographs, drawings and creative writing in the form of recipes. These are recipes in an expanded sense: imagined sets of instructions, lists, and conceptual ingredients enrich this book, which does more than cook your weekday meal. In its pages, twenty-two emerging writers and artists share instructions for meals remembered and commentary on food, community and nourishment." -- Publisher's website

Involvement of neuronal nitric oxide synthase in cross-sensitization between chronic unpredictable stress and ethanol in adolescent and adult mice.

The peculiar neurochemical profile of the adolescent brain renders it differently susceptible to several stimuli, including stress and/or drug exposure. Among several stress mediators, nitric oxide (NO) has a role in stress responses. We have demonstrated that adolescent mice are less sensitive to ethanol-induced sensitization than adult mice. The present study investigated whether chronic unpredictable stress (CUS) induces behavioral sensitization to ethanol in adolescent and adult Swiss mice, and investigated the influence of Ca2+-dependent nitric oxide synthase (NOS) activity in the phenomenon. Adolescent and adult mice were exposed to repeated 1.8&nbsp;g/kg ethanol or CUS and challenged with saline or ethanol. A neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7NI), was administered along with ethanol and CUS to test its effects on behavioral sensitization. Both adolescent and adult mice displayed cross-sensitization between CUS and ethanol in adult mice, with adolescents showing a lower degree of sensitization than adults. nNOS inhibition by 7NI reduced both ethanol sensitization and cross-sensitization. All age differences in the Ca2+-dependent NOS activity in the hippocampus and prefrontal cortex were in the direction of greater activity in adults than in adolescents. Adolescents showed lower sensitivity to cross-sensitization between CUS and ethanol, and the nitric oxide (NO) system seems to have a pivotal role in ethanol-induced behavioral sensitization and cross-sensitization in both adolescent and adult mice