A whole-cell killed unencapsulated pneumococcal vaccine given by the intranasal route with cholera toxin as an adjuvant was tested in two animal models. This vaccination was highly effective in preventing nasopharyngeal colonization with an encapsulated serotype 6B strain in mice and also conferred protection against illness and death in rats inoculated intrathoracically with a highly encapsulated serotype 3 strain. When the serotype 3 challenge strain was incubated in the sera of immunized rats, it was no longer virulent in an infant-rat sepsis model, indicating that the intranasal immunization elicited protective systemic antibodies. These studies suggest that killed whole-cell unencapsulated pneumococci given intranasally with an adjuvant may provide multitypic protection against capsulated pneumococci.Streptococcus pneumoniae (pneumococcus) annually causes 10 million deaths worldwide, including the deaths of 1 million children in low-income countries (26). Type-specific immunity, based on the capsular polysaccharides (PS), is well established (20). The licensed 23-valent PS vaccine, however, is not efficacious in children younger than 2 years. The newly licensed heptavalent PS conjugate vaccine protects against 90% of pneumococcal invasive disease in infancy in the United States (28) but includes fewer serotypes than the PS vaccine and omits several that are prevalent worldwide (10). Other drawbacks of the conjugate vaccine include a limited effect on otitis media (2, 11), high costs, and the potential for serotype replacement, which has already been suggested in recent clinical trials (11, 17; R. Dagan, N. Givon, P. Yagupsky, N. Porat, J. Janco, I. Chang, et al., Program Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. S52, 1998).Several investigators have identified protective antigens common to pneumococci of many or all serotypes. Several such "species" antigens in purified or vectored form have shown protection in animal models (4-6, 8, 18, 19, 23, 25), but it is uncertain whether, when, and at what cost any of these will be developed as an effective vaccine for humans, particularly in low-income countries. As an alternative presentation of species antigens, we have studied unencapsulated whole cells, which should present a number of such antigens in native configuration unoccluded by capsule. In addition, the intranasal route of immunization might elicit mucosal immunity and, with suitable adjuvant, systemic immunity as well. Finally, of importance to low-income countries, a mucosally administered whole-cell preparation has the possible advantage of low cost of production and administration, without the need for sterile injection devices. In the present study we tested killed, unencapsulated cells applied intranasally with cholera toxin (CT) as an adjuvant (R. Malley, S. Pelton, A. Stack, R. Saladino, D. E. Briles, and P. Anderson, 2nd Int. Symp. Pneumococci Pneumococcal Dis., abstr. P25, 2000), using two animal models: nasopharyngeal colonization of mice with type 6B and lethal intrat...

Objectives The emergency department (ED) is characterized by stressors (e.g. fatigue, stress, time-pressure, and complex decision-making) that can pose challenges to delivering high quality, equitable care. Although it has been suggested that characteristics of the ED may exacerbate reliance on cognitive heuristics, no research has directly investigated whether stressors in the ED impact physician racial bias, a common heuristic. We seek to determine if physicians have different levels of implicit racial bias post-ED shift versus pre-shift, and to examine associations between demographics and cognitive stressors with bias. Methods This repeated measures study of resident physicians in a pediatric ED used electronic pre- and post-shift assessments of implicit racial bias, demographics, and cognitive stressors. Implicit bias was measured using the Race Implicit Association Test (IAT). Linear regression models compared differences in IAT scores pre- to post-shift, and determined associations between participant demographics and cognitive stressors with post-shift IAT and pre- to post-shift difference scores. Results Participants (n=91) displayed moderate pro-white/anti-black bias on pre-shift (M=0.50, SD=0.34, d=1.48) and post-shift (M=0.55, SD=0.39, d=1.40) IAT scores. Overall, IAT scores did not differ pre-shift to post-shift (mean increase=0.05, 95% CI −0.02,0.14, d=0.13). Sub-analyses revealed increased pre- to post-shift bias among participants working when the ED was more overcrowded (mean increase=0.09, 95% CI 0.01,0.17, d=0.24) and among those caring for >10 patients (mean increase=0.17, 95% CI 0.05,0.27, d=0.47). Residents’ demographics (including specialty), fatigue, busyness, stressfulness, and number of shifts were not associated with post-shift IAT or difference scores. In multivariable models, ED overcrowding was associated with greater post-shift bias (coefficient=0.11 per 1 unit of NEDOCS score, SE=0.05, 95% CI 0.00,0.21). Conclusions While resident implicit bias remained stable overall pre-shift to post-shift, cognitive stressors (overcrowding and patient load) were associated with increased implicit bias. Physicians in the ED should be aware of how cognitive stressors may exacerbate implicit racial bias.

No transfusion reactions were reported. The median (IQR) time from ED admission to the start of the WB transfusion was 15 (14-77) minutes, compared with 303 (129-741) minutes (P < .001) for administration of at least 1 unit of RBCs, plasma, and platelets in the historical cohort (Figure).Discussion | To our knowledge, this is the first cohort of pediatric civilian trauma patients to receive WB during resuscitation. These preliminary data suggest that WB transfusion of up to 20 mL/kg is safe in children with severe injuries; there was no evidence of hemolysis in non-group O recipients, and no transfusion reactions were reported. Based on these data, the transfusion committee of Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center approved an increase in maximum volume of WB transfusion to 30 mL/kg. Larger cohorts are necessary for further study to determine if WB administration will affect outcomes, including number of donor exposures, cost, total volume transfused, and mortality.

Septic shock induced by lipopolysaccharide (LPS) triggering of cytokine production from monocytes/macrophages is a major cause of morbidity and mortality. The major monocyte/macrophage LPS receptor is the glycosylphosphatidylinositol (GPI)-anchored glycoprotein CD14. Here we demonstrate that CD14 coimmunoprecipitates with G i /G o heterotrimeric G proteins. Furthermore, we demonstrate that heterotrimeric G proteins specifically regulate CD14-mediated, LPS-induced mitogen-activated protein kinase (MAPK) activation and cytokine production in normal human monocytes and cultured cells. We report here that a G protein binding peptide protects rats from LPS-induced mortality, suggesting a functional linkage between a GPIanchored receptor and the intracellular signaling molecules with which it is physically associated. ( J. Clin. Invest. 1998 .