Acute Versus Delayed Surgical Intervention in Multiligament Knee Injuries: A Systematic Review.

BACKGROUND: The optimal timing of surgical intervention for multiligament knee injuries remains controversial. PURPOSE: To review the clinical and functional outcomes after acute and delayed surgical intervention for multiligament knee injuries. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: We performed a search of the PubMed, Embase, Cochrane Library, and Web of Science databases from inception to September 2020. Eligible studies reported on knee dislocations, multiligament knee injuries, or bicruciate ligament injuries in adult patients (age, ≥18 years). In addition to comparing outcomes between acute and delayed surgical intervention groups, we conducted 3 subgroup analyses for outcomes within isolated knee injuries, knee injuries with concomitant polytrauma/fractures, and high-level (level 2) studies. RESULTS: Included in the analysis were 31 studies, designated as evidence level 2 (n = 3), level 3 (n = 8), and level 4 (n = 20). These studies reported on 2594 multiligament knee injuries sustained by 2585 patients (mean age, 25.1-65.3 years; mean follow-up, 12-157.2 months). At the latest follow-up timepoint, the mean Lysholm (n = 375), International Knee Documentation Committee (IKDC) (n = 286), and Tegner (n = 129) scores for the acute surgical intervention group were 73.60, 67.61, and 5.06, respectively. For the delayed surgical intervention group, the mean Lysholm (n = 196), IKDC (n = 172), and Tegner (n = 74) scores were 85.23, 72.32, and 4.85, respectively. The mean Lysholm (n = 323), IKDC (n = 236), and Tegner (n = 143) scores for our isolated subgroup were 83.7, 74.8, and 5.0, respectively. By comparison, the mean Lysholm (n = 270), IKDC (n = 236), and Tegner (n = 206) scores for the polytrauma/fractures subgroup were 83.3, 64.5, and 5.0, respectively. CONCLUSION: The results of our systematic review did not elucidate whether acute or delayed surgical intervention produced superior clinical and functional outcomes. Although previous evidence has supported acute surgical intervention, future prospective randomized controlled trials and matched cohort studies must be completed to confirm these findings.

Trends of snowboarding-related fractures that presented to emergency departments in the United States, 2010 to 2016.

BACKGROUND: Since it was introduced as an Olympic sport in 1998, snowboarding has drawn the participation of individuals of all ages. Despite the growing popularity of this sport, individuals can suffer from a number of musculoskeletal injuries. The specific goals of the study were to: (I) compare the number of injuries and trends of snowboarding injuries; (II) identify the injury occurrences, trends, and incidence of snowboarding-related fractures; and (III) identify the injury occurrences and trends of snowboarding-related fractures by body part. METHODS: The National Electronic Injury Surveillance System (NEISS) database was queried for snowboarding injuries and snowboarding-related fractures treated in US emergency departments (EDs) from 2010-2016. The weighted estimate of the number of injuries were obtained by using the NEISS statistical weight calculations that were provided in the data. An estimated total of 248,388 patients (mean age =20 years) experienced a snowboarding-related injury. Linear regression analysis was used to analyze annual trends of snowboarding-related fractures and the snowboarding-related fractures by body part; reported as the correlation coefficient (r) and the coefficient of determination (R2). RESULTS: The estimated annual number of injuries decreased from 56,223 injuries in 2010 to 17,667 injuries in 2016 (r=-0.967, R2=0.936, P<0.001). The most common types of injuries were fractures (31.7%), strains/sprains (25.2%), contusions (10.9%), concussions (10.0%), internal injuries (7.2%), and dislocations (4.0%). From 2010 to 2016, the estimated annual number of fractures decreased from 18,757 in 2010 to 4,539 in 2016 (r=-0.978, R2=0.957, P<0.001), and the annual incidence of snowboarding-related fractures decreased by 23.1%. The most common location of snowboarding-related fractures was the upper extremity, more specifically the wrist (32.3%). There was a decrease in the estimated annual number of fractures of the wrist (r=-0.965, R2=0.932, P<0.001), forearm (r=-0.821, R2=0.861, P=0.023), shoulder (r=-0.872, R2=0.760, P=0.011), elbow (r=-0.901, R2=0.813, P=0.006), and lower leg (r=-0.929, R2=0.864, P=0.002). CONCLUSIONS: With the growing popularity of snowboarding in the US, it is important to know the common types of injuries that occur. This study found that fractures were the most common injuries, especially of the upper extremity.

Lagging skills contribute to challenging behaviors in children with autism spectrum disorder without intellectual disability.

Many children with autism spectrum disorder display challenging behaviors. These behaviors are not limited to those with cognitive and/or language impairments. The Collaborative and Proactive Solutions framework proposes that challenging behaviors result from an incompatibility between environmental demands and a child's "lagging skills." The primary Collaborative and Proactive Solutions lagging skills-executive function, emotion regulation, language, and social skills-are often areas of weakness for individuals with autism spectrum disorder. The purpose of this study was to evaluate whether these lagging skills are associated with challenging behaviors in youth with autism spectrum disorder without intellectual disability. Parents of 182 youth with autism spectrum disorder (6-15 years) completed measures of their children's challenging behaviors, executive function, language, emotion regulation, and social skills. We tested whether the Collaborative and Proactive Solutions lagging skills predicted challenging behaviors using multiple linear regression. The Collaborative and Proactive Solutions lagging skills explained significant variance in participants' challenging behaviors. The Depression (emotion regulation), Inhibit (executive function), and Sameness (executive function) scales emerged as significant predictors. Impairments in emotion regulation and executive function may contribute substantially to aggressive and oppositional behaviors in school-age youth with autism spectrum disorder without intellectual disability. Treatment for challenging behaviors in this group may consider targeting the incompatibility between environmental demands and a child's lagging skills.

Generation of Th17 cells in response to intranasal infection requires TGF-ß1 from dendritic cells and IL-6 from CD301b+ dendritic cells.

Intranasal (i.n.) infections preferentially generate Th17 cells. We explored the basis for this anatomic preference by tracking polyclonal CD4(+) T cells specific for an MHC class II-bound peptide from the mucosal pathogen Streptococcus pyogenes. S. pyogenes MHC class II-bound peptide-specific CD4(+) T cells were first activated in the cervical lymph nodes following i.n. inoculation and then differentiated into Th17 cells. S. pyogenes-induced Th17 formation depended on TGF-ß1 from dendritic cells and IL-6 from a CD301b(+) dendritic cell subset located in the cervical lymph nodes but not the spleen. Thus, the tendency of i.n. infection to induce Th17 cells is related to cytokine production by specialized dendritic cells that drain this site.

Influenza viral neuraminidase primes bacterial coinfection through TGF-ß-mediated expression of host cell receptors.

Influenza infection predisposes the host to secondary bacterial pneumonia, which is a major cause of mortality during influenza epidemics. The molecular mechanisms underlying the bacterial coinfection remain elusive. Neuraminidase (NA) of influenza A virus (IAV) enhances bacterial adherence and also activates TGF-ß. Because TGF-ß can up-regulate host adhesion molecules such as fibronectin and integrins for bacterial binding, we hypothesized that activated TGF-ß during IAV infection contributes to secondary bacterial infection by up-regulating these host adhesion molecules. Flow cytometric analyses of a human lung epithelial cell line indicated that the expression of fibronectin and α5 integrin was up-regulated after IAV infection or treatment with recombinant NA and was reversed through the inhibition of TGF-ß signaling. IAV-promoted adherence of group A Streptococcus (GAS) and other coinfective pathogens that require fibronectin for binding was prevented significantly by the inhibition of TGF-ß. However, IAV did not promote the adherence of Lactococcus lactis unless this bacterium expressed the fibronectin-binding protein of GAS. Mouse experiments showed that IAV infection enhanced GAS colonization in the lungs of wild-type animals but not in the lungs of mice deficient in TGF-ß signaling. Taken together, these results reveal a previously unrecognized mechanism: IAV NA enhances the expression of cellular adhesins through the activation of TGF-ß, leading to increased bacterial loading in the lungs. Our results suggest that TGF-ß and cellular adhesins may be potential pharmaceutical targets for the prevention of coinfection.

Robust antigen specific th17 T cell response to group A Streptococcus is dependent on IL-6 and intranasal route of infection.

Group A streptococcus (GAS, Streptococcus pyogenes) is the cause of a variety of clinical conditions, ranging from pharyngitis to autoimmune disease. Peptide-major histocompatibility complex class II (pMHCII) tetramers have recently emerged as a highly sensitive means to quantify pMHCII-specific CD4+ helper T cells and evaluate their contribution to both protective immunity and autoimmune complications induced by specific bacterial pathogens. In lieu of identifying an immunodominant peptide expressed by GAS, a surrogate peptide (2W) was fused to the highly expressed M1 protein on the surface of GAS to allow in-depth analysis of the CD4+ helper T cell response in C57BL/6 mice that express the I-A(b) MHCII molecule. Following intranasal inoculation with GAS-2W, antigen-experienced 2W:I-A(b)-specific CD4+ T cells were identified in the nasal-associated lymphoid tissue (NALT) that produced IL-17A or IL-17A and IFN-γ if infection was recurrent. The dominant Th17 response was also dependent on the intranasal route of inoculation; intravenous or subcutaneous inoculations produced primarily IFN-γ+ 2W:I-A(b+) CD4+ T cells. The acquisition of IL-17A production by 2W:I-A(b)-specific T cells and the capacity of mice to survive infection depended on the innate cytokine IL-6. IL-6-deficient mice that survived infection became long-term carriers despite the presence of abundant IFN-γ-producing 2W:I-A(b)-specific CD4+ T cells. Our results suggest that an imbalance between IL-17- and IFN-γ-producing CD4+ T cells could contribute to GAS carriage in humans.

Comprehensive analysis of antibody responses to streptococcal and tissue antigens in patients with acute rheumatic fever.

Acute rheumatic fever (ARF) is an autoimmune disease occurring in individuals following untreated group A streptococcal infection believed to be triggered by antibodies to bacterial components that cross-react with human tissues. We developed a multiplexed immunoassay for the simultaneous quantitation of antibodies to nine streptococcal-related antigens including streptolysin O (SLO), DNase B, collagen I and IV, fibronectin, myosin, group A carbohydrate, M6 protein and streptococcal C5a peptidase. Utilizing this method, we examined serum from 49 ARF, 58 pharyngitis patients and age- and sex-matched controls in samples collected at initial disease onset, and at 4 weeks, 6 months and 1 year after diagnosis. Antibody responses were significantly higher for SLO, DNase B, M6 protein, group A carbohydrate and the cross-reactive antigens collagen I and myosin in ARF compared with pharyngitis patients (P

Streptococcal modulation of cellular invasion via TGF-beta1 signaling.

Group A Streptococcus (GAS) and other bacterial pathogens are known to interact with integrins as an initial step in a complex pathway of bacterial ingestion by host cells. Efficient GAS invasion depends on the interaction of bound fibronectin (Fn) with integrins and activation of integrin signaling. TGF-beta1 regulates expression of integrins, Fn, and other extracellular matrix proteins, and positively controls the integrin signaling pathway. Therefore, we postulated that TGF-beta1 levels could influence streptococcal invasion of mammalian cells. Pretreatment of HEp-2 cells with TGF-beta1 increased their capacity to ingest GAS when the bacteria expressed fibronectin-binding proteins (M1 or PrtF1). Western blots revealed significant induction of alpha5 integrin and Fn expression by HEp-2 cells in response to TGF-beta1. Increased ingestion of streptococci by these cells was blocked by a specific inhibitor of the TGF-beta1 receptor I and antibodies directed against alpha5 integrin and Fn, indicating that increased invasion depends on TGF-beta1 up-regulation of both the alpha5 integrin and Fn. The capacity of TGF-beta1 to up-regulate integrin expression and intracellular invasion by GAS was reproduced in primary human tonsil fibroblasts, which could be a source of TGF-beta1 in chronically infected tonsils. The relationship between TGF-beta1 and GAS invasion was strengthened by the observation that TGF-beta1 production was stimulated in GAS-infected primary human tonsil fibroblasts. These findings suggest a mechanism by which GAS induce a cascade of changes in mammalian tissue leading to elevated expression of the alpha5beta1 receptor, enhanced invasion, and increased opportunity for survival and persistence in their human host.

Human immunogenicity studies on group A streptococcal C5a peptidase (SCPA) as a potential vaccine against group A streptococcal infections.

BACKGROUND & OBJECTIVES: Group A streptococcal C5a peptidase (SCPA) is a major virulence surface factor. Its highly conserved nature among all tested serotypes of group A streptococci (GAS) as well as animal protection studies make SCPA a prime vaccine candidate. The present study was undertaken to explore the human immunogenicity to SCPA using an indirect enzyme-linked immunosorbent assay. METHODS: Children (n=72) who had signs and symptoms of acute pharyngitis and had GAS isolated from the throat at initial visit were included. Acute and convalescent sera were collected 4 weeks apart. ELISA was performed using recombinant SCPA peptide as antigen. RESULTS: The mean convalescent anti-SCPA level was twice the level of mean acute anti-SCPA and the difference was statistically significant (P < 0.0001). There was a rise in convalescent anti-SCPA in all children aged 2-12 yr. INTERPRETATION & CONCLUSION: Our observations confirmed that SCPA was highly immunogenic in children infected with group A streptococcal pharyngitis. Further studies need to be done to characterize the immune response including antibody subclass.

Processing, stability, and kinetic parameters of C5a peptidase from Streptococcus pyogenes.

A recombinant streptococcal C5a peptidase was expressed in Escherichia coli and its catalytic properties and thermal stability were subjected to examination. It was shown that the NH2-terminal region of C5a peptidase (Asn32-Asp79/Lys90) forms the pro-sequence segment. Upon maturation the propeptide is hydrolyzed either via an autocatalytic intramolecular cleavage or by exogenous protease streptopain. At pH 7.4 the enzyme exhibited maximum activity in the narrow range of temperatures between 40 and 43 degrees C. The process of heat denaturation of C5a peptidase investigated by fluorescence and circular dichroism spectroscopy revealed that the protein undergoes biphasic unfolding transition with Tm of 50 and 70 degrees C suggesting melting of different parts of the molecule with different stability. Unfolding of the less stable structures was accompanied by the loss of proteolytic activity. Using synthetic peptides corresponding to the COOH-terminus of human complement C5a we demonstrated that in vitro peptidase catalyzes hydrolysis of two His67-Lys68 and Ala58-Ser59 peptide bonds. The high catalytic efficiency obtained for the SQLRANISHKDMQLGR extended peptide compared to the poor hydrolysis of its derivative Ac-SQLRANISH-pNA that lacks residues at P2'-P7' positions, suggest the importance of C5a peptidase interactions with the P' side of the substrate.

The group B streptococcal C5a peptidase is both a specific protease and an invasin.

The group B streptococcus (GBS) is a major cause of pneumonia, sepsis, and meningitis in neonates and a serious cause of mortality or morbidity in immunocompromised adults. Although these streptococci adhere efficiently and invade a variety of tissue-specific epithelial and endothelial cells, adhesins and invasins are still unknown. All serotypes of GBS studied to date express C5a peptidase (SCPB) on their surface. This investigation addresses the possibility that this relatively large surface protein has additional activities. Rabbit anti-SCPB serum inhibited invasion of lung epithelial A549 cells by the serotype Ia strain O90R, suggesting that SCPB is an invasin. This was confirmed by inserting an in-frame 25-amino-acid deletion into the scpB gene. Invasion of HEp2 and A549 human cell lines was significantly reduced by the mutation. Enzyme-linked immunosorbent assays were used to demonstrate that purified SCPB protein binds directly to HEp2 and A549 cells and also binds the extracellular matrix protein fibronectin. Binding was dose dependent and saturable. These results suggested that SCPB is one of several potential invasins essential for GBS colonization of damaged epithelium.

M(+) group a streptococci are phagocytized and killed in whole blood by C5a-activated polymorphonuclear leukocytes.

Historically, resistance to phagocytosis has been determined by incubating group A streptococci in human blood and comparing the numbers of CFU before and after incubation. Utilizing a flow cytometry-based technique, we have investigated the phagocytosis of M(+) group A streptococci by polymorphonuclear leukocytes (PMNs) in heparinized human peripheral whole blood. Intracellular labeling of streptococci with a nontoxic fluorescent dye allowed us to quantify the association and phagocytosis of M(+) streptococci by PMNs in whole blood in the presence or absence of C5a, a physiologically important chemotactic activator of PMNs. We found that wild-type strains of group A streptococci that are resistant to phagocytosis (determined by the classical Lancefield method) readily associate with C5a-activated whole-blood PMNs. In the absence of opsonizing M-type-specific antibodies, the M(+) streptococci associated with PMNs are phagocytized and killed. In addition, blockade of the beta(2) integrin, CD11b/CD18, with anti-human CD11b monoclonal antibody inhibited association between M(+) streptococci and C5a-activated PMNs. These findings establish a new relationship between M(+) streptococci and PMNs, in which C5a-activated PMNs have the capacity to kill M(+) streptococci in whole blood through a receptor-mediated phagocytic mechanism.