Severe Pediatric Neurological Manifestations With SARS-CoV-2 or MIS-C Hospitalization and New Morbidity

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery

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

Regulation of Expression of 5 Alpha-Reductase Type 1 in Mouse Leydig Cells

Testosterone is the principal androgen produced in the testis of most species. The enzyme 5a-reductase converts circulating testosterone to dihydrotestosterone in target tissues, a process that is necessary for development of the male phenotype in human beings. However, in some animals, androstanediol, a 5a-reduced androgen, is the primary androgen produced by the testis during certain stages of development, indicating the presence of 5a-reductase in the testis itself. Studies in mice show that while both isozymes of 5a-reductase are absent in the fetal and adult testis, 5a-reductase type 1 is the only form present in the immature (prepubertal) testicular Leydig cells when androstanediol is their principal product. The high testosterone production by the fetal and adult mouse testis is driven by human chorionic gonadotropin and luteinizing hormone, respectively, which act through elevation of intracellular cyclic AMP. Consequently, we hypothesized that 5a-reductase type 1 is constitutively present in the mouse Leydig cell and repressed by cyclic AMP. We screened two mouse Leydig cell lines: MLTC-1 cells&MA-10 cells, for 5a-reductase type 1 activity. Both cell lines expressed abundant 5a-reductase type 1 activity under basal conditions and mmetabolized progesterone to allopregnanolone, but MA-10 cells yielded additional products. Treatment of MLTC-1 cells with forskolin or human chorionic gonadotropin dramatically decreased 5a-reductase type 1 activity in the cells after 1 hour. Future experiments will address the mechanism of this effect, including the changes in transcription, translation, and degradatio

'Behind the measure of all things': Exploring the Case of a Psychometric Test to Measure Sexual Orientation in India

This paper examines the curious case of a psychometric scale to measure sexual orientation published in India post the decriminalization of homosexuality in 2018. Investigating the hermeneutical choices made by the developer of the scale in various stages of its construction, I argue that the scale’s treatment of sexual orientation as a measurable construct necessitates a politics of willfully sustained ignorance (Pohlhaus 2012). By carefully deploying the ignorance of queer lives and realities, the scale generates mistrust for self-disclosure, sanitizes sexual orientation of its socially deviant elements, and creates a straitjacket of sexual identities to override the agential power of the test-taking subject. Based on an evaluation of the unjust research practices embedded in the scale’s development, I suggest that there is a need to re-evaluate the ethical responsibilities of the scientist in generating knowledge about vulnerably situated groups

The Art of Sim-Making: What to Learn from Film-Making

The components of each stage have similarities as well as differences, which make each unique in its own right. As the film-making and the movie industry may have much we can learn from, some of these will be covered under the different sections of the paper, for example, Writing Powerful Narratives, depiction of emotional elements, specific industry-driven developments as well as the cultural considerations in both. For medical simulation and simulation-based education, the corresponding stages are as follows: DevelopmentPreproductionProductionPostproduction andDistribution. The art of sim-making has many similarities to that of film-making. In fact, there is potentially much to be learnt from the film-making process in cinematography and storytelling. Both film-making and sim-making can be seen from the artistic perspective as starting with a large piece of blank, white sheet of paper, which will need to be colored by the artists and personnel involved; in the former, to come up with the film and for the latter, to engage learners and ensure learning takes place, which is then translated into action for patients in the actual clinical care areas. Both entities have to go through a series of systematic stages. For film-making, the stages are as follows: Identification of problems and needs analysisSetting objectives, based on educational strategiesImplementation of the simulation activityDebriefing and evaluation, as well asFine-tuning for future use and archiving of scenarios/cases

The brain in pediatric critical care: unique aspects of assessment, monitoring, investigations, and follow-up

As survival after pediatric intensive care unit (PICU) admission has improved over recent years, a key focus now is the reduction of morbidities and optimization of quality of life for survivors. Neurologic disorders and direct brain injuries are the reason for 11-16% of admissions to PICU. In addition, many critically ill children are at heightened risk of brain injury and neurodevelopmental difficulties affecting later life, e.g., complex heart disease and premature birth. Hence, assessment, monitoring and protection of the brain, using fundamental principles of neurocritical care, are crucial to the practice of pediatric intensive care medicine. The assessment of brain function, necessary to direct appropriate care, is uniquely challenging amongst children admitted to the PICU. Challenges in assessment arise in children who are unstable, or pharmacologically sedated and muscle relaxed, or who have premorbid abnormality in development. Moreover, the heterogeneity of diseases and ages in PICU patients, means that high caliber evidence is harder to accrue than in adult practice, nonetheless, great progress has been made over recent years. In this 'state of the art' paper about critically ill children, we discuss (1) patient types at risk of brain injury, (2) new standardized clinical assessment tools for age-appropriate, clinical evaluation of brain function, (3) latest evidence related to cranial imaging, non-invasive and invasive monitoring of the brain, (4) the concept of childhood 'post intensive are syndrome' and approaches for neurodevelopmental follow-up. Better understanding of these concepts is vital for taking PICU survivorship to the next level