Rapid degradation and non-selectivity of Dakin's solution prevents effectiveness in contaminated musculoskeletal wound models.

BACKGROUND: Dakin's solution (buffered sodium hypochlorite) has been used as a topical adjunct for the treatment of invasive fungal infections in trauma patients. Prudent use of Dakin's solution (DS) for complex musculoskeletal wound management implies balancing antimicrobial efficacy and human tissue toxicity, but little empirical evidence exists to inform clinical practice. To identify potentially efficacious DS concentrations and application methods, we conducted two animal studies to evaluate the ability of DS to reduce bacterial burden in small and large animal models of contaminated musculoskeletal wounds. METHODS: An established rat (Rattus norvegicus) contaminated femoral defect model was employed to evaluate the antimicrobial efficacy of DS as a topical adjunctive treatment for Staphylococcus aureus infection. A range of clinically-relevant DS concentrations (0.00025%-0.125%) were tested, both with and without periodic replenishment during treatment. Next, an established goat (Capra hircus) musculoskeletal wound model, consisting of a Pseudomonas aeruginosa contaminated proximal tibia cortical defect, muscle crush, and thermal injury, was utilized to evaluate the antimicrobial efficacy of dilute DS (0.0025% and 0.025%) as a surgical irrigant solution. In situ reactive chlorine concentrations were monitored throughout each treatment using an automated iodometric titration approach. RESULTS: In a rat wound model, DS treatment did not significantly reduce S. aureus bioburden after 14 days as compared to saline control. Two treatment groups (0.01% single application and 0.025% multiple application) exhibited significantly higher bacterial burden than control. In a goat musculoskeletal wound model, neither 0.0025% nor 0.025% DS significantly altered P. aeruginosa bioburden immediately following treatment or at 48 h post-treatment. Overall, DS applied to exposed soft tissue exhibited rapid degradation, e.g., 0.125% DS degraded 32% after 5 s progressing to 86% degradation after 15 min following single application. CONCLUSIONS: We did not observe evidence of a therapeutic benefit following Dakin's solution treatment for any tested concentration or application method in two contaminated musculoskeletal wound models. Despite confirmation of robust bactericidal activity in vitro, our findings suggest DS at current clinically-used concentrations does not kill tissue surface-attached bacteria, nor does it necessarily cause host tissue toxicity that exacerbates infection in the setting of complex musculoskeletal injury.

Outcomes of Early Surgical Intervention in Geriatric Proximal Femur Fractures Among Patients Receiving Direct Oral Anticoagulation.

OBJECTIVE: To evaluate the prehospital use of direct oral anticoagulant (DOAC) agents on the outcomes of early surgical fixation of a geriatric hip fracture. DESIGN: Case control study. SETTING: Two academic Level 1 trauma centers. INTERVENTION: Early (<48 h) surgical fixation of a geriatric proximal femur fracture. PATIENTS: Nineteen patients receiving Pradaxa (dabigatran), Eliquis (apixaban), or Xarelto (rivaroxaban) who underwent surgery between 2010 and 2015 and 74 control patients. MAIN OUTCOME MEASUREMENTS: Time to surgery, transfusion rates, changes in hemoglobin levels, postoperative complications, readmission rates, and survival out to 1 year. RESULTS: There were no differences in transfusions, changes in hemoglobin levels, wound complications, or survival at any time point. Patients on DOAC had a longer delay to reach the operating room (28.9 h v 21.4 h P = 0.03) and were more likely to undergo readmission within 30 days (21% vs. 5.3% P = 0.05). No readmissions occurred for a complication of the surgical site, bleeding, or a venous thromboembolic event. CONCLUSIONS: Geriatric patients with hip fractures receiving DOAC before admission did not demonstrate worse outcomes with early surgical intervention. The increased readmission rate in this population seems attributable to the underlying cardiac conditions for which the patients were receiving anticoagulation. These results suggest that the delay recommended for patients using a DOAC before elective procedures may be unwarranted in the surgically urgent setting of a hip fracture. Additional studies will be necessary for appropriate meta-analysis. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Characteristics of US combat veterans (2001-2011) who remain on active duty after upper extremity amputations.

OBJECTIVES: Return to duty following traumatic amputations has been extensively studied in those with lower extremity amputation. As upper extremity amputations occur less frequently, the issue of return to duty for those with upper extremity amputations has received relatively little research. The purpose of this study was to determine the rate at which service members remain on active duty at least one year after having sustained traumatic upper extremity amputations during Operation Iraqi Freedom, Operation Enduring Freedom, and other overseas contingency operations of the Global War on Terrorism. DESIGN: Retrospective. SETTING: Military, Academic Level 1 trauma center. PATIENTS: One hundred eighteen patients who sustained combat-related upper extremity amputations between October 2001 and December 2011. INTERVENTION: Data was obtained from the medical record for these 118 patients. MAIN OUTCOME MEASUREMENTS: Percentage of service member remaining on active duty one year following an upper extremity amputation, and evaluation of demographic and injury related factors associated with retention. RESULTS: The overall rate for the upper extremity amputees studied at one year from injury who remained on active duty was 47%. Officers were more likely to remain on active duty than their enlisted counterparts (P=.021) and patients who sustained burns were also more likely to remain on active duty than patients with similar amputation types without concomitant burn injuries (P=.039). CONCLUSIONS: The rate of service members with traumatic upper extremity amputations who were still on active duty status 1-year postinjury was 47%. The presence of burns and rank were significant factors when examining retention on active duty. Further study on war casualties who sustain upper-extremity traumatic amputations with and without burns is required to optimize outcomes in this population.

CD70 and IFN-1 selectively induce eomesodermin or T-bet and synergize to promote CD8+ T-cell responses.

CD70-mediated stimulation of CD27 is an important cofactor of CD4(+) T-cell licensed dendritic cells (DCs). However, it is unclear how CD70-mediated stimulation of T cells is integrated with signals that emanate from signal 3 pathways, such as type-1 interferon (IFN-1) and IL-12. We find that while stimulation of CD27 in isolation drives weak Eomesodermin(hi) T-bet(lo) CD8(+) T-cell responses to OVA immunization, profound synergistic expansion is achieved by cotargeting TLR. This cooperativity can substantially boost antiviral CD8(+) T-cell responses during acute infection. Concomitant stimulation of TLR significantly increases per cell IFN-γ production and the proportion of the population with characteristics of short-lived effector cells, yet also promotes the ability to form long-lived memory. Notably, while IFN-1 contributes to the expression of CD70 on DCs, the synergy between CD27 and TLR stimulation is dependent upon IFN-1's effect directly on CD8(+) T cells, and is associated with the increased expression of T-bet in T cells. Surprisingly, we find that IL-12 fails to synergize with CD27 stimulation to promote CD8(+) T-cell expansion, despite its capacity to drive effector CD8(+) T-cell differentiation. Together, these data identify complex interactions between signal 3 and costimulatory pathways, and identify opportunities to influence the differentiation of CD8(+) T-cell responses.

CD27 stimulation promotes the frequency of IL-7 receptor-expressing memory precursors and prevents IL-12-mediated loss of CD8(+) T cell memory in the absence of CD4(+) T cell help.

Fully functional CD8(+) T cell memory is highly dependent upon CD4(+) T cell support. CD4(+) T cells play a critical role in inducing the expression of CD70, the ligand for CD27, on dendritic cells. In this study, we demonstrate that CD27 stimulation during primary CD8(+) T cell responses regulates the ability to mount secondary CD8(+) T cell responses. CD27 stimulation during vaccinia and dendritic cell immunization controls the expression of the IL-7R (CD127), which has been shown to be necessary for memory CD8(+) T cell survival. Furthermore, CD27 stimulation during primary CD8(+) T cell responses to vaccinia virus restrained the late expression on memory precursor cells of cytokine receptors that support terminal differentiation. The formation of CD8(+) T cell memory precursors and secondary CD8(+) T cell responses was restored in the absence of CD27 costimulation when endogenous IL-12 was not available. Similarly, the lesion in CD8(+) T cell memory that occurs in the absence of CD4(+) T cells did not occur in mice lacking IL-12. These data indicate that CD4(+) T cell help and, by extension, CD27 stimulation support CD8(+) T cell memory by modulating the expression of cytokine receptors that influence the differentiation and survival of memory CD8(+) T cells.

Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells.

The immune response to the tumor can be enhanced by targeting costimulatory molecules on T cells. As the CD70-CD27 costimulatory axis plays an important role in the activation, survival, and differentiation of lymphocytes, we have examined the efficacy of agonistic anti-CD27 antibodies as monotherapies for established melanoma in a murine model. We show that this approach leads to a substantial reduction in the outgrowth of both experimental lung metastases and subcutaneous tumors. Anti-CD27 treatment supports the maintenance of tumor-specific CD8(+) T cells within the tumor, reduces the frequency of FoxP3-expressing CD4(+) T cells within tumors, and potentiates the ability of NK1.1(+) and CD8(+) tumor infiltrating cells to secrete IFNγ upon coculture with tumor cells. The enhanced effector function correlated with lower levels of PD-1 expression on CD8(+) T cells from anti-CD27-treated mice. Despite the modulating effect of anti-CD27 on multiple cell types, only CD8(+) T cells were absolutely required for tumor control. The CD4(+) T cells were dispensable, whereas NK1.1(+) cells were needed during early stages of tumor growth but not for the effectiveness of anti-CD27. Thus, CD27-mediated costimulation provides a potent boost to multiple aspects of the endogenous responses to tumor, and may be exploited to enhance tumor immunity.