A glucan-particle based tularemia subunit vaccine induces T-cell immunity and affords partial protection in an inhalation rat infection model.

Tularemia is a zoonotic disease caused by the facultative intracellular gram-negative bacterium Francisella tularensis. F. tularensis has a very low infection dose by the aerosol route which can result in an acute, and potentially lethal, infection in humans. Consequently, it is classified as a Category A bioterrorism agent by the US Centers for Disease Control (CDC) and is a pathogen of concern for the International Biodefence community. There are currently no licenced tularemia vaccines. In this study we report on the continued assessment of a tularemia subunit vaccine utilising ß-glucan particles (GPs) as a vaccine delivery platform for immunogenic F. tularensis antigens. Using a Fischer 344 rat infection model, we demonstrate that a GP based vaccine comprising the F. tularensis lipopolysaccharide antigen together with the protein antigen FTT0814 provided partial protection of F344 rats against an aerosol challenge with a high virulence strain of F. tularensis, SCHU S4. Inclusion of imiquimod as an adjuvant failed to enhance protective efficacy. Moreover, the level of protection afforded was dependant on the challenge dose. Immunological characterisation of this vaccine demonstrated that it induced strong antibody immunoglobulin responses to both polysaccharide and protein antigens. Furthermore, we demonstrate that the FTT0814 component of the GP vaccine primed CD4+ and CD8+ T-cells from immunised F344 rats to express interferon-γ, and CD4+ cells to express interleukin-17, in an antigen specific manner. These data demonstrate the development potential of this tularemia subunit vaccine and builds on a body of work highlighting GPs as a promising vaccine platform for difficult to treat pathogens including those of concern to the bio-defence community.

Layering vaccination with antibiotic therapy results in protection and clearance of Burkholderia pseudomallei in Balb/c mice.

Melioidosis is a disease that is difficult to treat due to the causative organism, Burkholderia pseudomallei being inherently antibiotic resistant and it having the ability to invade, survive, and replicate in an intracellular environment. Combination therapy approaches are routinely being evaluated in animal models with the aim of improving the level of protection and clearance of colonizing bacteria detected. In this study, a subunit vaccine layered with the antibiotic finafloxacin was evaluated in vivo against an inhalational infection with B. pseudomallei in Balb/c mice. Groups of mice vaccinated, infected, and euthanized at antibiotic initiation had a reduced bacterial load compared to those that had not been immunized. In addition, the subunit vaccine provided a synergistic effect when it was delivered with a CpG ODN and finafloxacin was initiated at 48 h post-challenge. Vaccination was also shown to improve the outcome, in a composite measure of survival and clearance. In summary, layering a subunit vaccine with the antibiotic finafloxacin is a promising therapeutic alternative for use in the treatment of B. pseudomallei infections.

Predatory bacteria can protect SKH-1 mice from a lethal plague challenge.

With the rise of antimicrobial resistance, novel ways to treat bacterial infections are required and the use of predatory bacteria may be one such approach. Bdellovibrio species have been shown in vitro to predate on a wide range of other Gram-negative bacteria, including CDC category A/B pathogens such as Yersinia pestis. The data reported here show that treatment of SKH-1 mice with Bdellovibrio bacteriovorus HD100 provided significant protection from a lethal challenge of Yersinia pestis CO92. This is the first report of protection conferred by predation in vivo against a systemic pathogen challenge. However, this protective effect was not observed in a preliminary study with Balb/c mice. Therefore the effects of the predatory bacteria are complex and may be dependent on immune status/genetics of the host. Overall, predatory bacteria may have utility as a therapeutic modality but further work is required to understand the predator-host interaction.

Protection induced by a Francisella tularensis subunit vaccine delivered by glucan particles.

Francisella tularensis is an intracellular pathogen causing the disease tularemia, and an organism of concern to biodefence. There is no licensed vaccine available. Subunit approaches have failed to induce protection, which requires both humoral and cellular immune memory responses, and have been hampered by a lack of understanding as to which antigens are immunoprotective. We undertook a preliminary in silico analysis to identify candidate protein antigens. These antigens were then recombinantly expressed and encapsulated into glucan particles (GPs), purified Saccharomyces cerevisiae cell walls composed primarily of ß-1,3-glucans. Immunological profiling in the mouse was used to down-selection to seven lead antigens: FTT1043 (Mip), IglC, FTT0814, FTT0438, FTT0071 (GltA), FTT0289, FTT0890 (PilA) prior to transitioning their evaluation to a Fischer 344 rat model for efficacy evaluation. F344 rats were vaccinated with the GP protein antigens co-delivered with GP-loaded with Francisella LPS. Measurement of cell mediated immune responses and computational epitope analysis allowed down-selection to three promising candidates: FTT0438, FTT1043 and FTT0814. Of these, a GP vaccine delivering Francisella LPS and the FTT0814 protein was able to induce protection in rats against an aerosol challenge of F. tularensis SchuS4, and reduced organ colonisation and clinical signs below that which immunisation with a GP-LPS alone vaccine provided. This is the first report of a protein supplementing protection induced by LPS in a Francisella vaccine. This paves the way for developing an effective, safe subunit vaccine for the prevention of inhalational tularemia, and validates the GP platform for vaccine delivery where complex immune responses are required for prevention of infections by intracellular pathogens.

A Bioluminescent Francisella tularensis SCHU S4 Strain Enables Noninvasive Tracking of Bacterial Dissemination and the Evaluation of Antibiotics in an Inhalational Mouse Model of Tularemia.

Bioluminescence imaging (BLI) enables real-time, noninvasive tracking of infection in vivo and longitudinal infection studies. In this study, a bioluminescent Francisella tularensis strain, SCHU S4-lux, was used to develop an inhalational infection model in BALB/c mice. Mice were infected intranasally, and the progression of infection was monitored in real time using BLI. A bioluminescent signal was detectable from 3 days postinfection (3 dpi), initially in the spleen and then in the liver and lymph nodes, before finally becoming systemic. The level of bioluminescent signal correlated with bacterial numbers in vivo, enabling noninvasive quantification of bacterial burdens in tissues. Treatment with levofloxacin (commencing at 4 dpi) significantly reduced the BLI signal. Furthermore, BLI was able to distinguish noninvasively between different levofloxacin treatment regimens and to identify sites of relapse following treatment cessation. These data demonstrate that BLI and SCHU S4-lux are suitable for the study of F. tularensis pathogenesis and the evaluation of therapeutics for tularemia.

Multivariate Analysis of the Risk Factors for First-Time Noncontact ACL Injury in High School and College Athletes: A Prospective Cohort Study With a Nested, Matched Case-Control Analysis.

BACKGROUND: Multivariate analysis that identifies the combination of risk factors associated with anterior cruciate ligament (ACL) trauma is important because it provides insight into whether a variable has a direct causal effect on risk or an indirect effect that is mediated by other variables. It can also reveal risk factors that might not be evident in univariate analyses; if a variable's effect is moderated by other variables, its association with risk may be apparent only after adjustment for the other variables. Most important, multivariate analyses can identify combinations of risk factors that are more predictive of risk than individual risk factors. HYPOTHESIS: A diverse combination of risk factors predispose athletes to first-time noncontact ACL injury, and these relationships are different for male and female athletes. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Athletes competing in organized sports at the high school and college levels participated in this study. Data from injured subjects (109 suffering an ACL injury) and matched controls (227 subjects) from the same athletic team were analyzed with multivariate conditional logistic regression to examine the effects of combinations of variables (demographic characteristics, joint laxity, lower extremity alignment, strength, and personality traits) on the risk of suffering their first ACL injury and to construct risk models. RESULTS: For male athletes, increases in anterior-posterior displacement of the tibia relative to the femur (knee laxity), posterior knee stiffness, navicular drop, and a decrease in standing quadriceps angle were jointly predictive of suffering an ACL injury. For female athletes the combined effects of having a parent who had suffered an ACL injury and increases in anterior-posterior knee laxity and body mass index were predictive of ACL injury. CONCLUSION: Multivariate models provided more information about ACL injury risk than individual risk factors. Both male and female risk models included increased anterior-posterior knee laxity as a predictor of ACL injury but were otherwise dissimilar.

The Effects of Level of Competition, Sport, and Sex on the Incidence of First-Time Noncontact Anterior Cruciate Ligament Injury.

BACKGROUND: Anterior cruciate ligament (ACL) injuries are disabling and are associated with the early onset of posttraumatic osteoarthritis. Little is known regarding the incidence rate of first-time noncontact ACL injuries sustained during athletic events and how they are independently influenced by level of competition, type of sport, and the participant's sex. HYPOTHESIS: Level of competition (college or high school), type of sport (soccer, basketball, lacrosse, field hockey, football, rugby, volleyball), and the athlete's sex independently influence the incidence rate of first-time noncontact ACL injuries. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Between fall 2008 and spring 2012, first-time noncontact ACL injury data were collected from 8 colleges and 18 high schools across 7 sports. Athlete exposure was computed retrospectively using team rosters and numbers of scheduled practices and games. Injury incidence rates (IRs) were computed per 1000 athlete exposures. The independent effects of level of competition, sport, and sex on ACL injury risk were estimated by Poisson regression. RESULTS: Colleges reported 48 ACL injuries with 320,719 athlete exposures across all sports studied (IR = 0.150 per 1000 person-days), while high schools reported 53 injuries with 873,057 athlete exposures (IR = 0.061). After adjustment for differences in sport and sex, college athletes had a significantly higher injury risk than did high school athletes (adjusted relative risk [RR], 2.38; 95% CI, 1.55-3.54). The overall IR for female athletes was 0.112 compared with 0.063 for males. After adjustment for sport and level of play, females were more than twice as likely to have a first-time ACL injury compared with males (RR, 2.10; 95% CI, 1.34-3.27). With lacrosse as the reference group, risk of first-time noncontact ACL injury was significantly higher for soccer players (RR, 1.77) and for rugby players (RR, 2.23), independent of level of play and sex. CONCLUSION: An athlete's risk of having a first-time noncontact ACL injury is independently influenced by level of competition, the participant's sex, and type of sport, and there are no interactions between their effects. Female college athletes have the highest risk of having a first-time noncontact ACL injury among the groups studied.

Relationship Between the Risk of Suffering a First-Time Noncontact ACL Injury and Geometry of the Femoral Notch and ACL: A Prospective Cohort Study With a Nested Case-Control Analysis.

BACKGROUND: The morphometric characteristics of the anterior cruciate ligament (ACL) and the femoral intercondylar notch within which it resides have been implicated as risk factors for injuries to this important stabilizer of the knee. Prior research has produced equivocal results with differing methodologies, and consequently, it is unclear how these characteristics affect the injury risk in male and female patients. HYPOTHESIS: The morphometric characteristics of the ACL and femoral intercondylar notch are individually and independently associated with the risk of suffering a noncontact ACL injury, and these relationships are different in male and female patients. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Magnetic resonance imaging scans of the bilateral knees were obtained on 88 case-control pairs (27 male, 61 female) matched for age, sex, and participation on the same sports team. Patients had suffered a grade III, first-time, noncontact ACL tear. The femoral notch width at 4 locations, the thickness of the bony ridge at the anteromedial outlet of the femoral notch, the femoral notch volume, ACL volume, and ACL cross-sectional area were measured. RESULTS: Multivariate analysis of combined data from male and female patients revealed that decreased ACL volume (odds ratio [OR], 0.829), decreased femoral notch width (OR, 0.700), and increased bony ridge thickness at the anteromedial outlet of the femoral notch (OR, 1.614) were significant independent predictors of an ACL injury. Separate analyses of male and female patients indicated that the femoral notch ridge may be more strongly associated with a risk in female patients, while ACL volume is more strongly associated with a risk in male patients. However, statistical analysis performed with an adjustment for body weight strengthened the association between ACL volume and the risk of injuries in female patients. CONCLUSION: Morphometric features of both the ACL and femoral notch combine to influence the risk of suffering a noncontact ACL injury. When included together in a multivariate model that adjusts for body weight, the effects of the morphometric measurements are similar in male and female patients. If body weight is not taken into consideration, ACL volume is not associated with a risk in female patients.

Increased slope of the lateral tibial plateau subchondral bone is associated with greater risk of noncontact ACL injury in females but not in males: a prospective cohort study with a nested, matched case-control analysis.

BACKGROUND: There is an emerging consensus that increased posterior-inferior directed slope of the subchondral bone portion of the tibial plateau is associated with increased risk of suffering an anterior cruciate ligament (ACL) injury; however, most of what is known about this relationship has come from unmatched case-control studies. These observations need to be confirmed in more rigorously designed investigations. HYPOTHESIS: Increased posterior-inferior directed slope of the medial and lateral tibial plateaus are associated with increased risk of suffering a noncontact ACL injury. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: In sum, 176 athletes competing in organized sports at the college and high school levels participated in the study: 88 suffering their first noncontact ACL injury and 88 matched controls. Magnetic resonance images were acquired, and geometry of the subchondral bone portion of the tibial plateau was characterized on each athlete bilaterally by measuring the medial and lateral tibial plateau slopes, coronal tibial slope, and the depth of the medial tibial plateau. Comparisons between knees of the same person were made with paired t tests, and associations with injury risk were assessed by conditional logistic regression analysis of ACL-injured and control participants. RESULTS: Controls exhibited side-to-side symmetry of subchondral bone geometry, while the ACL-injured athletes did not, suggesting that the ACL injury may have changed the subchondral bone geometry. Therefore, the uninjured knees of the ACL-injured athletes and the corresponding limbs of their matched controls were used to assess associations with injury risk. Analyses of males and females as a combined group and females as a separate group showed a significant association between ACL injury risk and increased posterior-inferior directed slope of the lateral tibial plateau slope. This relationship was not apparent when males were analyzed as a group. Multivariate analyses indicated that these results were independent of the medial tibial plateau slope, coronal tibial slope, and depth of the medial tibial plateau, which were not associated with ACL injury. CONCLUSION: There is a 21.7% increased risk of noncontact ACL injury with each degree increase of the lateral tibial plateau slope among females but not among males. The medial tibial plateau slope, coronal tibial slope, and depth of the medial tibial plateau were not associated with risk of injury for females or males.

Geometric profile of the tibial plateau cartilage surface is associated with the risk of non-contact anterior cruciate ligament injury.

The purpose of this study was to determine if geometry of the articular surfaces of the tibial plateau is associated with non-contact anterior cruciate ligament (ACL) injury. This was a longitudinal cohort study with a nested case-control analysis. Seventy-eight subjects who suffered a non-contact ACL tear and a corresponding number of controls matched by age, sex, and sport underwent 3 T MRI of both knees. Surface geometry of the tibial articular cartilage was characterized with polynomial equations and comparisons were made between knees on the same person and between ACL-injured and control subjects. There was no difference in surface geometry between the knees of the control subjects. In contrast, there were significant differences in the surface geometry between the injured and normal knees of the ACL-injured subjects, suggesting that the ACL injury changed the cartilage surface profile. Therefore, comparisons were made between the uninjured knees of the ACL-injured subjects and the corresponding knees of their matched controls and this revealed significant differences in the surface geometry for the medial (p < 0.006) and lateral (p < 0.001) compartments. ACL-injured subjects tended to demonstrate a posterior-inferior directed orientation of the articular surface relative to the long axis of the tibia, while the control subjects were more likely to show a posterior-superior directed orientation.

Assessment of antimicrobial peptide LL-37 as a post-exposure therapy to protect against respiratory tularemia in mice.

Early activation of the innate immune response is important for protection against infection with Francisella tularensis live vaccine strain (LVS) in mice. The human cathelicidin antimicrobial peptide LL-37 is known to have immunomodulatory properties, and therefore exogenously administered LL-37 may be suitable as an early post-exposure therapy to protect against LVS infection. LL-37 has been evaluated for immunostimulatory activity in uninfected mice and for activity against LVS in macrophage assays and protective efficacy when administered post-challenge in a mouse model of respiratory tularemia. Increased levels of pro-inflammatory cytokine IL-6, chemokines monocyte chemoattractant protein 1 (MCP-1) and CXCL1 with increased neutrophil influx into the lungs were observed in uninfected mice after intranasal administration of LL-37. Following LVS challenge, LL-37 administration resulted in increased IL-6, IL-12 p70, IFNγ and MCP-1 production, a slowing of LVS growth in the lung, and a significant extension of mean time to death compared to control mice. However, protection was transient, with the LL-37 treated mice eventually succumbing to infection. As this short course of nasally delivered LL-37 was moderately effective at overcoming the immunosuppressive effects of LVS infection this suggests that a more sustained treatment regimen may be an effective therapy against this pathogen.

Reliability of a new stabilized dynamometer system for the evaluation of hip strength.

BACKGROUND: Hip strength is associated with numerous orthopaedic and neuromuscular injuries and/or pathologies and may be assessed with a variety of anatomic testing positions and techniques. Isokinetic dynamometers are generally too cumbersome and intricate for efficient use in mass screenings (for prognostic studies of risk for injury) as well as with special populations. The reliability of isometric testing devices has demonstrated varied reliability, generally examining only 1 or 2 motions of the hip and reporting values of force, not torque. Consequently, there is a need for an efficient hip strength-testing device to quantify torque that tests subjects in 1 anatomic position, while evaluating multiple hip motions. HYPOTHESIS: Evaluation of supine hip abduction, adduction, flexion, and extension torque using a new stabilized dynamometer system will produce good to excellent intra- and interexaminer reliability results. STUDY DESIGN: A blinded, randomized, repeated-measures study design was used in this descriptive laboratory investigation. METHODS: Supine isometric hip flexion, extension, abduction, and adduction torques were evaluated with a cage-stabilized dynamometer in 19 collegiate and professional-level ice hockey athletes by 2 investigators at 3 time intervals. Inter- and intrarater reliability was assessed. RESULTS: Supine hip flexion, extension, abduction, and adduction torque was performed with good to excellent inter- and intrarater reliability (intraclass correlation coefficients ranging from 0.74 to 0.92 and 0.78 to 0.92, respectively) for all motions tested. CONCLUSIONS: We have developed an isometric hip strength-testing device that can be assembled around an examination table to efficiently and reliably evaluate torque developed for multiple motions of the hip. CLINICAL RELEVANCE: This device and testing protocol may be used to efficiently evaluate hip strength in numerous settings; it allows decreased subject burden and increased comfort (which may be important following an injury in case-control investigations); and it may be well tolerated when testing athletes as well as special populations in the clinical setting.

Risk factors for anterior cruciate ligament injury: a review of the literature - part 1: neuromuscular and anatomic risk.

CONTEXT: Injuries to the anterior cruciate ligament (ACL) of the knee are immediately debilitating and can cause long-term consequences, including the early onset of osteoarthritis. It is important to have a comprehensive understanding of all possible risk factors for ACL injury to identify individuals who are at risk for future injuries and to provide an appropriate level of counseling and programs for prevention. OBJECTIVE: This review, part 1 of a 2-part series, highlights what is known and still unknown regarding anatomic and neuromuscular risk factors for injury to the ACL from the current peer-reviewed literature. DATA SOURCES: Studies were identified from MEDLINE (1951-March 2011) using the MeSH terms anterior cruciate ligament, knee injury, and risk factors. The bibliographies of relevant articles and reviews were cross-referenced to complete the search. STUDY SELECTION: Prognostic studies that utilized the case-control and prospective cohort study designs to evaluate risk factors for ACL injury were included in this review. RESULTS: A total of 50 case-control and prospective cohort articles were included in the review, and 30 of these studies focused on neuromuscular and anatomic risk factors. CONCLUSIONS: Several anatomic and neuromuscular risk factors are associated with increased risk of suffering ACL injury-such as female sex and specific measures of bony geometry of the knee joint, including decreased intercondylar femoral notch size, decreased depth of concavity of the medial tibial plateau, increased slope of the tibial plateaus, and increased anterior-posterior knee laxity. These risk factors most likely act in combination to influence the risk of ACL injury; however, multivariate risk models that consider all the aforementioned risk factors in combination have not been established to explore this interaction.

Risk factors for anterior cruciate ligament injury: a review of the literature-part 2: hormonal, genetic, cognitive function, previous injury, and extrinsic risk factors.

CONTEXT: Injuries to the anterior cruciate ligament (ACL) are immediately disabling and are associated with long-term consequences, such as posttraumatic osteoarthritis. It is important to have a comprehensive understanding of all possible risk factors for ACL injury to identify individuals who are at risk for future injuries and to provide an appropriate level of counseling and programs for prevention. OBJECTIVE: This review, part 2 of a 2-part series, highlights what is known and still unknown regarding hormonal, genetic, cognitive function, previous injury, and extrinsic risk factors for ACL injury. DATA SOURCES: Studies were identified from MEDLINE (1951-March 2011) using the MeSH terms anterior cruciate ligament, knee injury, and risk factors. The bibliographies of relevant articles and reviews were cross-referenced to complete the search. STUDY SELECTION: Prognostic case-control and prospective cohort study designs to evaluate risk factors for ACL injury were included in this review. RESULTS: A total of 50 case-control and prospective cohort articles were included in parts 1 and 2. Twenty-one focused on hormonal, genetic, cognitive function, previous injury, and extrinsic risk factors. CONCLUSIONS: Several risk factors are associated with increased risk of suffering ACL injury-such as female sex, prior reconstruction of the ACL, and familial predisposition. These risk factors most likely act in combination with the anatomic factors reviewed in part 1 of this series to influence the risk of suffering ACL injury.

Application of a clinic-based algorithm as a tool to identify female athletes at risk for anterior cruciate ligament injury: a prospective cohort study with a nested, matched case-control analysis.

BACKGROUND: When landing from a jump, the production of increased intersegmental knee abduction moments and coupled valgus motions has been associated with an increased risk of suffering a noncontact anterior cruciate ligament (ACL) injury in one study. This research has led to the development of a clinic-based algorithm that utilizes measures of knee valgus motion, knee flexion range of motion, body mass, tibial length, and quadriceps-to-hamstring strength ratio data to predict the probability of a high knee abduction moment (pKAM) when landing from a jump in female athletes. The ability of this algorithm to identify athletes at increased risk of suffering ACL injury has not been assessed. HYPOTHESIS: The pKAM is associated with ACL injury in female athletes. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: This study was based on secondary analysis of data obtained from a previous investigation that focused on the use of the drop vertical jump (DVJ) test to assess the risk of ACL injury in female athletes. The DVJ screenings were performed on 1855 female high school and college athletes over 3 years. Knee valgus motion, knee flexion range of motion, and tibial length were measured from videos of the DVJ obtained during preseason screenings. Mass was measured using a physician's scale, and quadriceps-to-hamstring strength ratio was included using a surrogate value. These data were entered into the clinic-based algorithm that determined the pKAM. The association of pKAM with ACL injury was assessed using conditional logistic regression. RESULTS: A total of 20 athletes sustained ACL injury and were matched with 45 uninjured control athletes who were recruited from the same teams. There was no relationship between the risk of suffering ACL injury and pKAM, as determined by the clinic-based algorithm. CONCLUSION: The pKAM was not associated with noncontact ACL injury in our group of injured athletes and matched controls.

A Toll/interleukin (IL)-1 receptor domain protein from Yersinia pestis interacts with mammalian IL-1/Toll-like receptor pathways but does not play a central role in the virulence of Y. pestis in a mouse model of bubonic plague.

The Toll/interleukin (IL)-1 receptor (TIR) domain is an essential component of eukaryotic innate immune signalling pathways. Interaction between TIR domains present in Toll-like receptors and associated adaptors initiates and propagates an immune signalling cascade. Proteins containing TIR domains have also been discovered in bacteria. Studies have subsequently shown that these proteins are able to modulate mammalian immune signalling pathways dependent on TIR interactions and that this may represent an evasion strategy for bacterial pathogens. Here, we investigate a TIR domain protein from the highly virulent bacterium Yersinia pestis, the causative agent of plague. When overexpressed in vitro this protein is able to downregulate IL-1ß- and LPS-dependent signalling to NFκB and to interact with the TIR adaptor protein MyD88. This interaction is dependent on a single proline residue. However, a Y. pestis knockout mutant lacking the TIR domain protein was not attenuated in virulence in a mouse model of bubonic plague. Minor alterations in the host cytokine response to the mutant were indicated, suggesting a potential subtle role in pathogenesis. The Y. pestis mutant also showed increased auto-aggregation and reduced survival in high-salinity conditions, phenotypes which may contribute to pathogenesis or survival.

A prospective evaluation of the Landing Error Scoring System (LESS) as a screening tool for anterior cruciate ligament injury risk.

BACKGROUND: Anterior cruciate ligament (ACL) injuries are immediately disabling, costly, take a significant amount of time to rehabilitate, and are associated with an increased risk of developing posttraumatic osteoarthritis of the knee. Specific multiplanar movement patterns of the lower extremity, such as those associated with the drop vertical jump (DVJ) test, have been shown to be associated with an increased risk of suffering noncontact ACL injuries. The Landing Error Scoring System (LESS) has been developed as a tool that can be applied to identify individuals who display at-risk movement patterns during the DVJ. HYPOTHESIS: An increase in LESS score is associated with an increased risk of noncontact ACL injury. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Over a 3-year interval, 5047 high school and college participants performed preseason DVJ tests that were recorded using commercial video cameras. All participants were followed for ACL injury during their sports season, and video data from injured participants and matched controls were then assessed with the LESS. Conditional logistic regression analysis was used to examine the association between LESS score and ACL injury risk in all participants as well as subgroups of female, male, high school, and college participants. RESULTS: There was no relationship between the risk of suffering ACL injury and LESS score whether measured as a continuous or a categorical variable. This was the case for all participants combined (odds ratio, 1.04 per unit increase in LESS score; 95% confidence interval, 0.80-1.35) as well as within each subgroup (odds ratio range, 0.99-1.14). CONCLUSION: The LESS did not predict ACL injury in our cohort of high school and college athletes.

An anthrax subunit vaccine candidate based on protective regions of Bacillus anthracis protective antigen and lethal factor.

Studies have confirmed the key role of Bacillus anthracis protective antigen (PA) in the US and UK human anthrax vaccines. However, given the tripartite nature of the toxin, other components, including lethal factor (LF), are also likely to contribute to protection. We examined the antibody and T cell responses to PA and LF in human volunteers immunized with the UK anthrax vaccine (AVP). Individual LF domains were assessed for immunogenicity in mice when given alone or with PA. Based on the results obtained, a novel fusion protein comprising D1 of LF and the host cell-binding domain of PA (D4) was assessed for protective efficacy. Murine protection studies demonstrated that both full-length LF and D1 of LF conferred complete protection against a lethal intraperitoneal challenge with B. anthracis STI spores. Subsequent studies with the LFD1-PAD4 fusion protein showed a similar level of protection. LF is immunogenic in humans and is likely to contribute to the protection stimulated by AVP. A single vaccine comprising protective regions from LF and PA would simplify production and confer a broader spectrum of protection than that seen with PA alone.

Small protective fragments of the Yersinia pestis V antigen.

Yersinia pestis is the causative agent of plague. Naturally occurring cases of the disease and the potential use of Y. pestis as a bioweapon fuel the need for efficacious vaccines. The most recent plague vaccine is a killed whole cell preparation that is expensive to manufacture and its side effects are common. The protective antigens F1 and V have been identified and are currently being developed as a combined subunit vaccine. Protective epitopes of the V antigen have previously been shown to reside in the central part of the protein. In order to identify the minimum protective fragment of the V antigen that can provide protection against plague, the structures of several small fragments of the antigen were modelled in silico and recombinant proteins were produced. These fragments were probed for the retention of a protective epitope using a protective monoclonal antibody and protection against Y. pestis in mice was determined. The smallest protective fragment of V antigen identified comprised amino acids 135-262. Finally the ability of this fragment to confer protection when given in the context of a DNA vaccine was confirmed.