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Background: To evaluate the immunogenicity of the inactivated herpes-zoster vaccine HZ/su in patients at increased risk for VZV-reactivation, we analysed the quantity and quality of the vaccine-induced cellular and humoral immunity in patients on dialysis with uremic immunodeficiency., Methods: In this observational study, 29 patients and 39 immunocompetent controls underwent standard dual-dose vaccination. Blood samples were analysed before and two weeks after each vaccination, and after one year. Specific T-cells were characterized after stimulation with VZV-gE-peptides based on induction of cytokines and CTLA-4-expression using flow-cytometry. Antibodies were analysed using ELISA., Findings: Both groups showed an increase in VZV-gE-specific CD4 T-cell levels over time (p < 0.0001), although median levels reached after second vaccination were lower in patients (0.17% (IQR 0.21%)) than in controls (0.24% (IQR 0.3%), p = 0.042). VZV-gE specific CD8 T-cells were only poorly induced. CTLA-4 expression on VZV-gE-specific CD4 T-cells was strongest after second dose with no differences between the groups (p = 0.45). Multifunctional cells co-expressing IFNγ, IL-2, and TNF were higher in patients after first vaccination (p = 0.028). Median VZV-specific IgG-levels reached a maximum after second vaccination with significantly lower levels in patients (10796 (IQR 12482) IU/l) than in controls (16899 (IQR 14019) IU/l, p = 0.009). Despite similar CD4 T-cell levels after one year (p = 0.415), antibody levels remained significantly lower in patients (p = 0.0008)., Interpretation: VZV-gE vaccination induced specific antibodies and CD4 T-cells in both patients and controls, whereas CD8 T-cell-induction was poor. Quantitative and qualitative differences in immunity may indicate reduced duration of protection which may necessitate booster vaccinations in patients on dialysis., Funding: HOMFORexzellent (to D.S.)., Competing Interests: Declaration of interests M.S. has received grant support from Astellas and Biotest to the organization Saarland University outside the submitted work, and honoraria for lectures from Biotest and Novartis, and for advisory boards from Moderna, Biotest, MSD and Takeda outside the submitted work. T.S. has received travel grant support from Biotest outside the submitted work. All other authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Peripheral facial palsy (PFP) is a common neurologic symptom which can be triggered by pathogens, autoimmunity, trauma, tumors, cholesteatoma or further local conditions disturbing the peripheral section of the nerve. In general, its cause is often difficult to identify, remaining unknown in over two thirds of cases. As we have previously shown that the quantity and quality of pathogen-specific T cells change during active infections, we hypothesized that such changes may also help to identify the causative pathogen in PFPs of unknown origin., Methods: In this observational study, pathogen-specific T cells were quantified in blood samples of 55 patients with PFP and 23 healthy controls after stimulation with antigens from varicella-zoster virus (VZV), herpes-simplex viruses (HSV) or borrelia. T cells were further characterized by expression of the inhibitory surface molecule CTLA-4, as well as markers for differentiation (CD27) and proliferation (Ki67). Pathogen-specific antibody responses were analyzed using ELISA. Results were compared with conventional diagnostics., Results: Patients with PFP were more often HSV-seropositive than controls (p = 0.0003), whereas VZV- and borrelia-specific antibodies did not differ between groups. Although the quantity and general phenotypical characteristics of antigen-specific T cells did not differ either, expression of CTLA-4 and Ki67 was highly increased in VZV-specific T cells of 9 PFP patients, of which 5 showed typical signs of cutaneous zoster. In the remaining 4 patients, a causal relationship with VZV was possible but remained unclear by clinical standard diagnostics. A similar CTLA-4- and Ki67-expression profile of borrelia-specific T cells was also found in a patient with acute neuroborreliosis., Discussion: In conclusion, the high prevalence of HSV-seropositivity among PFP-patients may indicate an underestimation of HSV-involvement in PFP, even though HSV-specific T cell characteristics seem insufficient to identify HSV as a causative agent. In contrast, striking alterations in VZV- and borrelia-specific T cell phenotype and function may allow identification of VZV- and borrelia-triggered PFPs. If confirmed in larger studies, antigen-specific immune-phenotyping may have the potential to improve specificity of the clinical diagnosis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Parkinson's disease (PD) emerges as a complex, multifactorial disease. While there is increasing evidence that dysregulated T cells play a central role in PD pathogenesis, elucidation of the pathomechanical changes in related signaling is still in its beginnings. We employed time-resolved RNA expression upon the activation of peripheral CD4+ T cells to track and functionally relate changes on cellular signaling in representative cases of patients at different stages of PD. While only few miRNAs showed time-course related expression changes in PD, we identified groups of genes with significantly altered expression for each different time window. Towards a further understanding of the functional consequences, we highlighted pathways with decreased or increased activity in PD, including the most prominent altered IL-17 pathway. Flow cytometric analyses showed not only an increased prevalence of Th17 cells but also a specific subtype of IL-17 producing γδ-T cells, indicating a previously unknown role in PD pathogenesis., (© 2023. The Author(s).)

Comparative analyses of the immunogenicity and reactogenicity of homologous and heterologous SARS-CoV-2 vaccine-regimens will inform optimized vaccine strategies. Here we analyze the humoral and cellular immune response following heterologous and homologous vaccination strategies in a convenience cohort of 331 healthy individuals. All regimens induce immunity to the vaccine antigen. Immunity after vaccination with ChAdOx1-nCoV-19 followed by either BNT162b2 (n = 66) or mRNA-1273 (n = 101) is equivalent to or more pronounced than homologous mRNA-regimens (n = 43 BNT162b2, n = 59 mRNA-1273) or homologous ChAdOx1-nCoV-19 vaccination (n = 62). We note highest levels of spike-specific CD8 T-cells following both heterologous regimens. Among mRNA-containing combinations, spike-specific CD4 T-cell levels in regimens including mRNA-1273 are higher than respective combinations with BNT162b2. Polyfunctional T-cell levels are highest in regimens based on ChAdOx1-nCoV-19-priming. All five regimens are well tolerated with most pronounced reactogenicity upon ChAdOx1-nCoV-19-priming, and ChAdOx1-nCoV-19/mRNA-1273-boosting. In conclusion, we present comparative analyses of immunogenicity and reactogenicity for heterologous vector/mRNA-boosting and homologous mRNA-regimens., (© 2022. The Author(s).)

SARS-CoV-2 infection is associated with an increased rate of thromboembolic events and mortality. Different vaccines are globally used to limit the pandemic. In this report, we present the case of two young female patients with newly diagnosed cerebral sinus vein thrombosis occurring after injection of the vector-based ChAdOx1 vaccine. Both patients presented with unusual headache only. The two of them used an estrogen-containing contraception, had had a history of deep venous thrombosis, and both had MTHFR mutations. Both patients developed SARS-CoV-2 specific humoral and cellular immunity including both CD4 and CD8 T cells. This rare, but serious complication needs to be considered after vaccination of young females, even if there is no evidence of heparin-induced thrombocytopenia., (© 2021. The Author(s).)

Knowledge on the immunogenicity of vector-based and mRNA-vaccines in solid organ transplant recipients is limited. Therefore, SARS-CoV-2-specific T cells and antibodies were analyzed in 40 transplant recipients and 70 controls after homologous or heterologous vaccine-regimens. Plasmablasts and SARS-CoV-2-specific CD4 and CD8 T cells were quantified using flow cytometry. Specific antibodies were analyzed by ELISA and neutralization assay. The two vaccine types differed after the first vaccination, as IgG and neutralizing activity were more pronounced after mRNA priming (p = .0001 each), whereas CD4 and CD8 T cell levels were higher after vector priming (p = .009; p = .0001). All regimens were well tolerated, and SARS-CoV-2-specific antibodies and/or T cells after second vaccination were induced in 100% of controls and 70.6% of transplant recipients. Although antibody and T cell levels were lower in patients, heterologous vaccination led to the most pronounced induction of antibodies and CD4 T cells. Plasmablast numbers were significantly higher in controls and correlated with SARS-CoV-2-specific IgG- and T cell levels. While antibodies were only detected in 35.3% of patients, cellular immunity was more frequently found (64.7%) indicating that assessment of antibodies is insufficient to identify COVID-19-vaccine responders. In conclusion, heterologous vaccination seems promising in transplant recipients, and combined analysis of humoral and cellular immunity improves the identification of responders among immunocompromised individuals., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Cervical cancer therapy is still a major clinical challenge, as patients substantially differ in their response to standard treatments, including chemoradiotherapy (CRT). During cervical carcinogenesis, T-helper (Th)-17 cells accumulate in the peripheral blood and tumor tissues of cancer patients and are associated with poor prognosis. In this prospective study, we find increased Th17 frequencies in the blood of patients after chemoradiotherapy and a post-therapeutic ratio of Th17/CD4 + T cells > 8% was associated with early recurrence. Furthermore, Th17 cells promote resistance of cervical cancer cells toward CRT, which was dependent on the AKT signaling pathway. Consistently, patients with high Th17 frequencies in pretherapeutic biopsies exhibit lower response to primary CRT. This work reveals a key role of Th17 cells in CRT resistance and elevated Th17 frequencies in the blood after CRT correspond with early recurrence. Our results may help to explain individual treatment responses of cervical cancer patients and suggest evaluation of Th17 cells as a novel predictive biomarker for chemoradiotherapy responses and as a potential target for immunotherapy in cervical cancer., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Heterologous priming with the ChAdOx1 nCoV-19 vector vaccine followed by boosting with a messenger RNA vaccine (BNT162b2 or mRNA-1273) is currently recommended in Germany, although data on immunogenicity and reactogenicity are not available. In this observational study we show that, in healthy adult individuals (n = 96), the heterologous vaccine regimen induced spike-specific IgG, neutralizing antibodies and spike-specific CD4 T cells, the levels of which which were significantly higher than after homologous vector vaccine boost (n = 55) and higher or comparable in magnitude to homologous mRNA vaccine regimens (n = 62). Moreover, spike-specific CD8 T cell levels after heterologous vaccination were significantly higher than after both homologous regimens. Spike-specific T cells were predominantly polyfunctional with largely overlapping cytokine-producing phenotypes in all three regimens. Recipients of both the homologous vector regimen and the heterologous vector/mRNA combination reported greater reactogenicity following the priming vector vaccination, whereas heterologous boosting was well tolerated and comparable to homologous mRNA boosting. Taken together, heterologous vector/mRNA boosting induces strong humoral and cellular immune responses with acceptable reactogenicity profiles., (© 2021. The Author(s).)

BACKGROUNDPatients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ in the severity of disease. We hypothesized that characteristics of SARS-CoV-2-specific immunity correlate with disease severity.METHODSIn this study, SARS-CoV-2-specific T cells and antibodies were characterized in uninfected controls and patients with different coronavirus disease 2019 (COVID-19) disease severity. SARS-CoV-2-specific T cells were flow cytometrically quantified after stimulation with SARS-CoV-2 peptide pools and analyzed for expression of cytokines (IFN-γ, IL-2, and TNF-α) and markers for activation, proliferation, and functional anergy. SARS-CoV-2-specific IgG and IgA antibodies were quantified using ELISA. Moreover, global characteristics of lymphocyte subpopulations were compared between patient groups and uninfected controls.RESULTSDespite severe lymphopenia affecting all major lymphocyte subpopulations, patients with severe disease mounted significantly higher levels of SARS-CoV-2-specific T cells as compared with convalescent individuals. SARS-CoV-2-specific CD4+ T cells dominated over CD8+ T cells and closely correlated with the number of plasmablasts and SARS-CoV-2-specific IgA and IgG levels. Unlike in convalescent patients, SARS-CoV-2-specific T cells in patients with severe disease showed marked alterations in phenotypical and functional properties, which also extended to CD4+ and CD8+ T cells in general.CONCLUSIONGiven the strong induction of specific immunity to control viral replication in patients with severe disease, the functionally altered characteristics may result from the need for contraction of specific and general immunity to counteract excessive immunopathology in the lung.FUNDINGThe study was supported by institutional funds to MS and in part by grants of Saarland University, the State of Saarland, and the Rolf M. Schwiete Stiftung.

T cells are central to the immune response against various pathogens and cancer cells. Complex networks of transcriptional and post-transcriptional regulators, including microRNAs (miRNAs), coordinate the T cell activation process. Available miRNA datasets, however, do not sufficiently dissolve the dynamic changes of miRNA controlled networks upon T cell activation. Here, we established a quantitative and time-resolved expression pattern for the entire miRNome over a period of 24 h upon human T-cell activation. Based on our time-resolved datasets, we identified central miRNAs and specified common miRNA expression profiles. We found the most prominent quantitative expression changes for miR-155-5p with a range from initially 40 molecules/cell to 1600 molecules/cell upon T-cell activation. We established a comprehensive dynamic regulatory network of both the up- and downstream regulation of miR-155. Upstream, we highlight IRF4 and its complexes with SPI1 and BATF as central for the transcriptional regulation of miR-155. Downstream of miR-155-5p, we verified 17 of its target genes by the time-resolved data recorded after T cell activation. Our data provide comprehensive insights into the range of stimulus induced miRNA abundance changes and lay the ground to identify efficient points of intervention for modifying the T cell response., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objectives: Influenza vaccination was used to assess whether induction of immunity or side effects are influenced by the timing of the last training session before vaccination., Methods: Forty-five healthy athletes (36 male, 23 ± 8 yr, ≥5 training sessions per week, predominantly national competition level) were vaccinated with the tetravalent influenza vaccine; blood samples were collected immediately before and 1, 2, and 26 wk after vaccination. Athletes were randomly assigned to vaccination within 2 h after the last training session versus after 24-26 h. Influenza-specific T cells were quantified after stimulation with the vaccine based on intracellular cytokine staining. Antibodies (IgA, IgG, IgM) were quantified by enzyme-linked immunosorbent assay and neutralization assay. Participants documented resulting side effects and training restrictions using a standardized diary., Results: Both groups showed an increase in influenza-reactive CD4 T-cell levels, which peaked 1 wk after vaccination (fold changes to baseline; median (interquartile range), 3.7 (3.0-5.4; P < 0.001) in the 2-h group; 4.6 (2.8-7.4; P < 0.001) in the 26-h group) with no difference between groups (P = 0.52). Influenza-specific antibodies showed a significant increase after vaccination in both groups (at least 1.4-fold, each P < 0.001, no group differences; P = 0.24-0.97 for different antibody types). Only antibodies toward the Brisbane strain showed a trend toward significant differences in neutralization titers between groups (4-fold (2-17.8) in the 2-h group, 16-fold (4-32.9) in the 26-h group; P = 0.06), whereas other specificities did not differ (P = 0.16-0.72). No intergroup differences were found for side effects; no athlete reported a loss of training time due to the vaccination or its side effects., Conclusion: Infection prophylaxis in elite athletes by influenza vaccination seems to be effective and safe. Timing of vaccination after prior training does not seem to require specific constraints.

Compliance of elite athletes with vaccination recommendations is low mainly based on concerns about side-effects and perceived poor vaccine efficacy due to continued physical training. We therefore employed seasonal influenza vaccination to investigate the effect of regular physical training on vaccine-induced cellular and humoral immunity in elite athletes and controls. Lymphocyte subpopulations and vaccine-specific T-cells were quantified and functionally characterized from 45 athletes and 25 controls before, and 1, 2 and 26 weeks after vaccination. Moreover, influenza-specific antibodies and their neutralizing function were quantified. Both groups showed a significant increase in vaccine-reactive CD4 T-cell levels which peaked one week after vaccination (p < 0.0001). The increase was significantly more pronounced in athletes (4.1-fold) compared to controls (2.3-fold; p = 0.0007). The cytokine profile changed from multifunctional T-cells co-producing IFNγ, IL-2 and TNFα to cells with restricted cytokine expression. This change in functionality was associated with a significant increase in CTLA-4 expression (p < 0.0001), which again was more pronounced in athletes. Likewise, the increase in neutralizing antibodies was stronger in athletes (p = 0.004 for H1N1; p = 0.032 for H3N2). In conclusion, both groups mounted a strong vaccine-specific cellular and humoral immunity after standard vaccination. The more pronounced increase in specific T-cells and neutralizing antibodies indicates that high frequency and intensity of training enhance vaccine-responses in elite athletes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Varicella zoster virus (VZV)-specific cellular immunity is essential for viral control, and the incidence of VZV reactivation is increased in patients with rheumatic diseases. Because knowledge of the influence of antirheumatic drugs on specific cellular immunity is limited, we analyzed VZV-specific T cells in patients with rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA), and we assessed how their levels and functionality were impacted by disease-modifying antirheumatic drugs (DMARDs). A polyclonal stimulation was carried out to analyze effects on general effector T cells., Methods: CD4 T cells in 98 blood samples of patients with RA (n = 78) or SpA (n = 20) were quantified by flow cytometry after stimulation with VZV antigen and the polyclonal stimulus Staphylococcus aureus enterotoxin B (SEB), and they were characterized for expression of cytokines (interferon-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-2) and markers for activation (CD69), differentiation (CD127), or functional anergy programmed death 1 molecule [PD-1], cytotoxic T-lymphocyte antigen 4 [CTLA-4]. Results of patients with RA were stratified into subgroups receiving different antirheumatic drugs and compared with samples of 39 healthy control subjects. Moreover, direct effects of biological DMARDs on cytokine expression and proliferation of specific T cells were analyzed in vitro., Results: Unlike patients with SpA, patients with RA showed significantly lower percentages of VZV-specific CD4 T cells (median 0.03%, IQR 0.05%) than control subjects (median 0.09%, IQR 0.16%; p < 0.001). Likewise, SEB-reactive CD4 T-cell levels were lower in patients (median 2.35%, IQR 2.85%) than in control subjects (median 3.96%, IQR 4.38%; p < 0.05); however, expression of cytokines and cell surface markers of VZV-specific T cells did not differ in patients and control subjects, whereas SEB-reactive effector T cells of patients showed signs of functional impairment. Among antirheumatic drugs, biological DMARDs had the most pronounced impact on cellular immunity. Specifically, VZV-specific CD4 T-cell levels were significantly reduced in patients receiving TNF-α antagonists or IL-6 receptor-blocking therapy (p < 0.05 and p < 0.01, respectively), whereas SEB-reactive T-cell levels were reduced in patients receiving B-cell-depleting or IL-6 receptor-blocking drugs (both p < 0.05)., Conclusions: Despite absence of clinical symptoms, patients with RA showed signs of impaired cellular immunity that affected both VZV-specific and general effector T cells. Strongest effects on cellular immunity were observed in patients treated with biological DMARDs. These findings may contribute to the increased susceptibility of patients with RA to VZV reactivation.

In this approach, pre-stained cells from extrasanguinous fluids (ESFs) are stimulated in the presence of blood from the same individual. Thus, blood-derived antigen-presenting cells enable stimulation of both ESF- and blood T cells. Pre-staining allows distinction of T cells from ESF and blood, and simultaneous analysis of antigen-specific T cells in both compartments., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Anterior cruciate ligament (ACL) injuries are prevalent in contact sports that feature cutting and pivoting, such as American football. These injuries typically require surgical treatment, can result in significant missed time from competition, and may have deleterious long-term effects on an athlete's playing career and health. While the majority of ACL tears in other sports have been shown to occur from a noncontact mechanism, it stands to reason that a significant number of ACL tears in American football would occur after contact, given the nature of the sport. Hypothesis/Purpose: The purpose was to describe the mechanism, playing situation, and lower extremity limb position associated with ACL injuries in professional American football players through video analysis to test the hypothesis that a majority of injuries occur via a contact mechanism., Study Design: Case series; Level of evidence, 4., Methods: A retrospective cohort of National Football League (NFL) players with ACL injuries from 3 consecutive seasons (2013-2016) was populated by searching publicly available online databases and other traditional media sources. Of 156 ACL injuries identified, 77 occurred during the regular season and playoffs, with video analysis available for 69 injuries. The video of each injury was independently viewed by 2 reviewers to determine the nature of the injury (ie, whether it occurred via a noncontact mechanism), the position of the lower extremity, and the football activity at the time of injury. Playing surface, player position, and time that the injury occurred were also recorded., Results: Contrary to our hypothesis, the majority of ACL injuries occurred via a noncontact mechanism (50 of 69, 72.5%), with the exception of injury to offensive linemen, who had a noncontact mechanism in only 20% of injuries. For noncontact injuries, the most common football activity at the time of injury was pivoting/cutting, and the most common position of the injured extremity included hip abduction/flexion, early knee flexion/abduction, and foot abduction/external rotation. There was no association between injury mechanism and time of injury or playing surface in this cohort., Conclusion: In this study of players in the NFL, the majority of ACL tears involved a noncontact mechanism, with the lower extremity exhibiting a dynamic valgus moment at the knee. These findings suggest that ACL injury prevention programs may reduce the risk of noncontact ACL tears in American football players.

VZV-reactivation may lead to symptomatic central nervous system (CNS) diseases, but identification of VZV as causative pathogen of CNS-diseases is challenging. This study was performed to characterize VZV-specific T cells from cerebrospinal fluid (CSF) and blood of patients with active CNS-disease and to determine whether this may improve differential diagnosis. 27 patients with pleocytosis in the CSF were recruited and classified into three groups (10 VZV-related, 10 non-VZV-related, 7 unclear). VZV-specific CD4 + T cells were quantified in CSF and blood after simultaneous stimulation with a VZV-antigen lysate and detection of cytokines (IFN-γ, IL-2, TNF-α) and CTLA-4. Polyclonal stimulation served as positive control. VZV-specific CD4 + T-cell frequencies were highest in both CSF (p = 0.0001) and blood (p = 0.011) of patients with VZV-infection, and were enriched at the site of infection (p = 0.002). While cytokine-expression profiles only showed minor differences between the groups, CTLA-4-expression levels on VZV-specific T cells from CSF and blood were significantly increased in VZV-related CNS-infections (p = 0.0002 and p<0.0001) and clearly identified VZV-related CNS-diseases (100% sensitivity and 100% specificity). Polyclonally stimulated T cells did not show any quantitative and phenotypical differences between the groups. Increased frequency and CTLA-4-expression of VZV-specific T cells from CSF or blood are specifically found in patients with VZV-related CNS-infection., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Varicella zoster virus (VZV) establishes lifelong persistence and may reactivate in individuals with impaired immune function. To investigate immunologic correlates of protection and VZV reactivation, we characterized specific immunity in 207 nonsymptomatic immunocompetent and 132 immunocompromised individuals in comparison with patients with acute herpes zoster., Methods: VZV-specific CD4 T cells were quantified flow cytometrically after stimulation and characterized for expression of interferon-γ, interleukin 2, and tumor necrosis factor α and surface markers for differentiation (CD127) and anergy (cytotoxic T lymphocyte antigen 4 [CTLA-4] and programmed death [PD]-1). Immunoglobulin G and A levels were quantified using an enzyme-linked immunosorbent assay., Results: In healthy individuals, VZV-specific antibody and T-cell levels were age dependent, with the highest median VZV-specific CD4 T-cell frequencies of 0.108% (interquartile range, 0.121%) during adolescence. VZV-specific T-cell profiles were multifunctional with predominant expression of all 3 cytokines, CD127 positivity, and low expression of CTLA-4 and PD-1. Nonsymptomatic immunocompromised patients had similar VZV-specific immunologic properties except for lower T-cell frequencies (P<.001) and restricted cytokine expression. In contrast, significantly elevated antibody- and VZV-specific CD4 T-cell levels were found in patients with zoster. Their specific T cells showed a shift in cytokine expression toward interferon γ single positivity, an increase in CTLA-4 and PD-1, and a decrease in CD127 expression (all P<.001). This phenotype normalized after resolution of symptoms., Conclusions: VZV-specific CD4-T cells in patients with zoster bear typical features of anergy. This phenotype is reversible and may serve as adjunct tool for monitoring VZV reactivations in high-risk patients., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Injuries to the pediatric and adolescent athlete are becoming more common as increasing numbers of this patient population are participating in year-round sporting activities. As these figures continue to rise, there have been an escalating number of patients with both traumatic and nontraumatic, sports-related knee injuries presenting to orthopedic surgeons for evaluation. Anterior cruciate ligament injuries in these patients, specifically in the skeletally immature, represent a complex problem. Treatment of these patients requires a thorough understanding of anatomy and physiology of the pediatric patient, the natural history of this injury, and knowledge of the potential complications of surgical intervention. This review will address these topics and will describe the presentation, diagnosis, and most commonly used surgical techniques currently being used with these patients. Future directions and advances in care of these injuries will also be discussed.

Introduction: Extensor tendon irritation and attritional tendon ruptures are potentially serious complications after open reduction and internal fixation of distal radius fractures. These complications are well recognized after dorsal plating of distal radii; and these are now being reported after errant screw placement during volar fixed-angle plating. Intraoperative detection of improper screw placement is critical, as corrective action can be taken before completion of the operative procedure. The purpose of this study was to define the extensor tendon compartments at risk secondary to dorsal screw penetration and to compare pronation and supination fluoroscopic images with standard lateral images in demonstrating dorsal screw prominence during volar locked plating., Methods: Eight fresh-frozen human cadaveric upper extremities underwent fixation with a volar, fixed-angle distal radius locked plate (Wright Medical Technology, Arlington, TN). Three fluoroscopic views (lateral, supinated, and pronated) followed by dorsal wrist dissections were compared to determine accuracy in detecting dorsal screw prominence and extensor tendon compartment violation. Subsequently, screws measuring 2, 4, 6, 8, and 10(mm longer than the measured depths were sequentially inserted into each distal locking screw, with each image deemed either "in" (completely inside the bone) or "out" (prominent screw tip dorsally-would typically be exchanged for a shorter screw intraoperatively)., Results: The radial most distal locking screw (position 1) violated either the first (25%) or second (75%) extensor tendon compartments. The average screw prominence required for radiographic detection was: 6.5(mm for lateral views and 2(mm for supinated views. Pronated views did not identify prominent screws. Screws occupying plate position 2 consistently entered Lister's tubercle, with 5/8 exiting the apex and 3/8 exiting the radial base. The average screw prominences for radiographic detection were: 2.75(mm-lateral views and 3.0(mm-supinated views. Although the screws entered the second dorsal compartment, they did not encroach upon either of the tendons. Screws occupying plate position 3 violated the third extensor tendon compartment in 7/8 specimens with 1/8 exiting the Ulan base of Lister's tubercle. The average screw prominences for radiographic detection were: 3.5(mm-lateral views and 2.5(mm-pronated views. Supinated views did not identify prominent hardware. Screws occupying plate position 4 all violated the IV dorsal extensor compartment-2/8 screws were noted to tent the posterior interosseous nerve. The average screw prominences required for radiographic detection were: 4.0(mm-lateral views and 2.5(mm-pronated views. The supinated views did not identify prominent screws., Conclusions: Volar fixed-angle plating has shown great promise in the advancement of distal radius fracture management. We have seen in our referral practices and in the literature an increase in the number of extensor tendon complications arising from unrecognized dorsally prominent screws, pegs, or tines. Standard PA and lateral radiographs cannot adequately visualize screw position and length secondary to the complex geometry of the dorsal cortex. We believe this study supports the routine application of intraoperative, oblique pronosupination fluoroscopic imaging for enhanced confirmation of distal locking screw position and length.