Protection by and maintenance of CD4 effector memory and effector T cell subsets in persistent malaria infection.

Protection at the peak of Plasmodium chabaudi blood-stage malaria infection is provided by CD4 T cells. We have shown that an increase in Th1 cells also correlates with protection during the persistent phase of malaria; however, it is unclear how these T cells are maintained. Persistent malaria infection promotes protection and generates both effector T cells (Teff), and effector memory T cells (Tem). We have previously defined new CD4 Teff (IL-7Rα-) subsets from Early (TeffEarly, CD62LhiCD27+) to Late (TeffLate, CD62LloCD27-) activation states. Here, we tested these effector and memory T cell subsets for their ability to survive and protect in vivo. We found that both polyclonal and P. chabaudi Merozoite Surface Protein-1 (MSP-1)-specific B5 TCR transgenic Tem survive better than Teff. Surprisingly, as Tem are associated with antigen persistence, Tem survive well even after clearance of infection. As previously shown during T cell contraction, TeffEarly, which can generate Tem, also survive better than other Teff subsets in uninfected recipients. Two other Tem survival mechanisms identified here are that low-level chronic infection promotes Tem both by driving their proliferation, and by programming production of Tem from Tcm. Protective CD4 T cell phenotypes have not been precisely determined in malaria, or other persistent infections. Therefore, we tested purified memory (Tmem) and Teff subsets in protection from peak pathology and parasitemia in immunocompromised recipient mice. Strikingly, among Tmem (IL-7Rαhi) subsets, only TemLate (CD62LloCD27-) reduced peak parasitemia (19%), though the dominant memory subset is TemEarly, which is not protective. In contrast, all Teff subsets reduced peak parasitemia by more than half, and mature Teff can generate Tem, though less. In summary, we have elucidated four mechanisms of Tem maintenance, and identified two long-lived T cell subsets (TemLate, TeffEarly) that may represent correlates of protection or a target for longer-lived vaccine-induced protection against malaria blood-stages.

Prospective derivation of a clinical decision rule for thoracolumbar spine evaluation after blunt trauma: An American Association for the Surgery of Trauma Multi-Institutional Trials Group Study.

BACKGROUND: Unlike the cervical spine (C-spine), where National Emergency X-Radiography Utilization Study (NEXUS) and the Canadian C-spine Rules can be used, evidence-based thoracolumbar spine (TL-spine) clearance guidelines do not exist. The aim of this study was to develop a clinical decision rule for evaluating the TL-spine after injury. METHODS: Adult (≥15 years) blunt trauma patients were prospectively enrolled at 13 US trauma centers (January 2012 to January 2014). Exclusion criteria included the following: C-spine injury with neurologic deficit, preexisting paraplegia/tetraplegia, and unevaluable examination. Remaining evaluable patients underwent TL-spine imaging and were followed up to discharge. The primary end point was a clinically significant TL-spine injury requiring TL-spine orthoses or surgical stabilization. Regression techniques were used to develop a clinical decision rule. Decision rule performance in identifying clinically significant fractures was tested. RESULTS: Of 12,479 patients screened, 3,065 (24.6%) met inclusion criteria (mean [SD] age, 43.5 [19.8] years [range, 15-103 years]; male sex, 66.3%; mean [SD] Injury Severity Score [ISS], 8.8 [7.5]). The majority underwent computed tomography (93.3%), 6.3% only plain films, and 0.2% magnetic resonance imaging exclusively. TL-spine injury was identified in 499 patients (16.3%), of which 264 (8.6%) were clinically significant (29.2% surgery, 70.8% TL-spine orthosis). The majority was AO Type A1 282 (56.5%), followed by 67 (13.4%) A3, 43 (8.6%) B2, and 32 (6.4%) A4 injuries. The predictive ability of clinical examination (pain, midline tenderness, deformity, neurologic deficit), age, and mechanism was examined; positive clinical examination finding resulted in a sensitivity of 78.4% and a specificity of 72.9%. Addition of age of 60 years or older and high-risk mechanism (fall, crush, motor vehicle crash with ejection/rollover, unenclosed vehicle crash, auto vs. pedestrian) increased sensitivity to 98.9% with specificity of 29.0% for clinically significant injuries and 100.0% sensitivity and 27.3% specificity for injuries requiring surgery. CONCLUSION: Clinical examination alone is insufficient for determining the need for imaging in evaluable patients at risk of TL-spine injury. Addition of age and high-risk mechanism results in a clinical decision-making rule with a sensitivity of 98.9% for clinically significant injuries. LEVEL OF EVIDENCE: Diagnostic test, level III.