PD-L1-PD-1 interactions limit effector regulatory T cell populations at homeostasis and during infection.

Phenotypic and transcriptional profiling of regulatory T (Treg) cells at homeostasis reveals that T cell receptor activation promotes Treg cells with an effector phenotype (eTreg) characterized by the production of interleukin-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eTreg cell activity, whereas during infection with Toxoplasma gondii, early interferon-γ upregulates myeloid cell expression of PD-L1 associated with reduced Treg cell populations. In infected mice, blockade of PD-L1, complete deletion of PD-1 or lineage-specific deletion of PD-1 in Treg cells prevents loss of eTreg cells. These interventions resulted in a reduced ratio of pathogen-specific effector T cells: eTreg cells and increased levels of interleukin-10 that mitigated the development of immunopathology, but which could compromise parasite control. Thus, eTreg cell expression of PD-1 acts as a sensor to rapidly tune the pool of eTreg cells at homeostasis and during inflammatory processes.

Impact of secondary TCR engagement on the heterogeneity of pathogen-specific CD8+ T cell response during acute and chronic toxoplasmosis.

Initial TCR engagement (priming) of naive CD8+ T cells results in T cell expansion, and these early events influence the generation of diverse effector and memory populations. During infection, activated T cells can re-encounter cognate antigen, but how these events influence local effector responses or formation of memory populations is unclear. To address this issue, OT-I T cells which express the Nur77-GFP reporter of TCR activation were paired with the parasite Toxoplasma gondii that expresses OVA to assess how secondary encounter with antigen influences CD8+ T cell responses. During acute infection, TCR stimulation in affected tissues correlated with parasite burden and was associated with markers of effector cells while Nur77-GFP- OT-I showed signs of effector memory potential. However, both Nur77-GFP- and Nur77-GFP+ OT-I from acutely infected mice formed similar memory populations when transferred into naive mice. During the chronic stage of infection in the CNS, TCR activation was associated with large scale transcriptional changes and the acquisition of an effector T cell phenotype as well as the generation of a population of CD103+ CD69+ Trm like cells. While inhibition of parasite replication resulted in reduced effector responses it did not alter the Trm population. These data sets highlight that recent TCR activation contributes to the phenotypic heterogeneity of the CD8+ T cell response but suggest that this process has a limited impact on memory populations at acute and chronic stages of infection.

ALK1 controls hepatic vessel formation, angiodiversity, and angiocrine functions in hereditary hemorrhagic telangiectasia of the liver.

BACKGROUND AND AIMS: In hereditary hemorrhagic telangiectasia (HHT), severe liver vascular malformations are associated with mutations in the Activin A Receptor-Like Type 1 ( ACVRL1 ) gene encoding ALK1, the receptor for bone morphogenetic protein (BMP) 9/BMP10, which regulates blood vessel development. Here, we established an HHT mouse model with exclusive liver involvement and adequate life expectancy to investigate ALK1 signaling in liver vessel formation and metabolic function. APPROACH AND RESULTS: Liver sinusoidal endothelial cell (LSEC)-selective Cre deleter line, Stab2-iCreF3 , was crossed with Acvrl1 -floxed mice to generate LSEC-specific Acvrl1 -deficient mice ( Alk1HEC-KO ). Alk1HEC-KO mice revealed hepatic vascular malformations and increased posthepatic flow, causing right ventricular volume overload. Transcriptomic analyses demonstrated induction of proangiogenic/tip cell gene sets and arterialization of hepatic vessels at the expense of LSEC and central venous identities. Loss of LSEC angiokines Wnt2 , Wnt9b , and R-spondin-3 ( Rspo3 ) led to disruption of metabolic liver zonation in Alk1HEC-KO mice and in liver specimens of patients with HHT. Furthermore, prion-like protein doppel ( Prnd ) and placental growth factor ( Pgf ) were upregulated in Alk1HEC-KO hepatic endothelial cells, representing candidates driving the organ-specific pathogenesis of HHT. In LSEC in vitro , stimulation or inhibition of ALK1 signaling counter-regulated Inhibitors of DNA binding (ID)1-3, known Alk1 transcriptional targets. Stimulation of ALK1 signaling and inhibition of ID1-3 function confirmed regulation of Wnt2 and Rspo3 by the BMP9/ALK1/ID axis. CONCLUSIONS: Hepatic endothelial ALK1 signaling protects from development of vascular malformations preserving organ-specific endothelial differentiation and angiocrine signaling. The long-term surviving Alk1HEC-KO HHT model offers opportunities to develop targeted therapies for this severe disease.

Management of transient bone osteoporosis: a systematic review.

INTRODUCTION: Transient bone osteoporosis (TBO) is characterized by persistent pain, loss of function, no history of trauma and magnetic resonance image (MRI) findings of bone marrow edema. SOURCE OF DATA: PubMed, Google scholar, EMABSE and Web of Science were accessed in February 2023. No time constrains were used for the search. AREAS OF AGREEMENT: TBO is rare and misunderstood, typically affecting women during the third trimester of pregnancy or middle-aged men, leading to functional disability for 4-8 weeks followed by self-resolution of the symptoms. AREAS OF CONTROVERSY: Given the limited evidence in the current literature, consensus on optimal management is lacking. GROWING POINTS: This systematic review investigates current management of TBO. AREAS TIMELY FOR DEVELOPING RESEARCH: A conservative approach leads to the resolution of symptoms and MRI findings at midterm follow-up. Administration of bisphosphonates might alleviate pain and accelerate both clinical and imaging recovery.

Evaluation of an electronic clinical decision support system (DeSSBack) to improve low back pain management: a pilot cluster randomized controlled trial.

BACKGROUND: Low back pain (LBP) is a common reason for primary care consultation; yet doctors often find managing it challenging. An electronic decision support system for LBP (DeSSBack) was developed based on an evidence-based risk stratification tool to improve the management of patients with LBP in a Malaysian primary care setting. This pilot study aimed to assess the feasibility, acceptability, and preliminary effectiveness of DeSSBack for the conduct of a future definitive trial. METHODS: A pilot cluster randomized controlled trial (cRCT) with qualitative interviews was conducted. Each primary care doctor was considered a cluster and randomized to either the control (usual practice) or intervention (DeSSBack) group. Patient outcomes including Roland-Morris Disability Questionnaire (RMDQ), Hospital Anxiety and Depression Scale, and a 10-point pain rating scale were measured at baseline and 2-month postintervention. The doctors in the intervention group were interviewed to explore feasibility and acceptability of using DeSSBack. RESULTS: Thirty-six patients with nonspecific LBP participated in this study (intervention n = 23; control n = 13). Fidelity was poor among patients but good among doctors. The RMDQ and anxiety score had medium effect sizes of 0.718 and 0.480, respectively. The effect sizes for pain score (0.070) and depression score were small (0.087). There was appreciable acceptability and satisfaction with use of DeSSBack, as it was helpful in facilitating thorough and standardized management, providing appropriate treatment plans based on risk stratification, improving consultation time, empowering patient-centred care, and easy to use. CONCLUSIONS: A future cRCT to evaluate the effectiveness of DeSSBack is feasible to be conducted in a primary care setting with minor modifications. DeSSBack was found useful by doctors and can be improved to enhance efficiency. TRIAL REGISTRATION: The protocol of the cluster randomized controlled trial was registered at ClinicalTrials.gov (NCT04959669).

Meniscectomy is associated with a higher rate of osteoarthritis compared to meniscal repair following acute tears: a meta-analysis.

PURPOSE: Meniscal tears are common and may impair knee function and biomechanics. This meta-analysis compared meniscal repair versus resection in patients with symptomatic meniscal tears in terms of patient-reported outcomes measures (PROMs), joint width, surgical failure, and rate of progression to osteoarthritis (OA) at conventional radiography. METHODS: This study was conducted according to the 2020 PRISMA statement. In August 2023, the following databases were accessed: PubMed, Web of Science, Google Scholar, and Embase. Two reviewers independently performed the analysis and a methodological quality assessment of the included studies. All the clinical investigations which compared repair versus resection of meniscal tears were accessed. RESULTS: Data from 20 studies (31,783 patients) were collected. The mean BMI was 28.28 ± 3.2 kg/m2, and the mean age was 37.6 ± 14.0 years. The mean time elapsed from injury to surgery was 12.1 ± 10.2 months and the mean medial joint width was 4.9 ± 0.8 mm. Between studies comparability at baseline was found in age, women, BMI, time from injury to surgery and length of the follow-up, PROMs, medial joint width, and stage of OA. The resection group demonstrated a greater Lysholm score (P = 0.02). No difference was found in the International Knee Documentation Committee (P = 0.2). Nine studies reported data on the rate of failures at a mean of 63.00 ± 24.7 months. No difference was found between the two groups in terms of persistent meniscal symptoms (P = 0.8). Six studies reported data on the rate of progression to total knee arthroplasty at a mean of 48.0 ± 14.7 months follow-up. The repair group evidenced a lower rate of progression to knee arthroplasty (P = 0.0001). Six studies reported data on the rate of advanced knee OA at a mean of 48.0 ± 14.7 months of follow-up. The repair group evidenced a lower rate of advanced knee OA (P = 0.0001). No difference was found in the mean joint space width (P = 0.09). CONCLUSION: Meniscal repair is associated with a lower progression to knee osteoarthritis at approximately six years of follow-up compared to partial meniscectomy. No difference in PROMs, medial joint width, and failures were evidenced. LEVEL OF EVIDENCE: Level III, meta-analysis.

Autologous chondrocyte implantation in the knee is effective in skeletally immature patients: a systematic review.

PURPOSE: This systematic review evaluated the efficacy and safety of autologous chondrocyte implantation (ACI) for chondral defects of the knee in skeletally immature patients. Current available data from patients reported outcome measures (PROMs) and complications were collected, analyzed, and discussed. METHODS: This systematic review was conducted according to the PRISMA guidelines. The following databases were accessed in May 2022: PubMed, Google scholar, Embase, and Scopus. All the clinical studies investigating the efficacy of ACI to manage chondral defects of the knee in skeletally immature patients were accessed. Articles treating patients with surgical procedures other than ACI were not eligible, nor were studies with a follow-up shorter than 12 months. RESULTS: Data from 9 studies (251 procedures) were collected. 32% (80 of 251) of patients were females. The mean length of follow-up was 44.2 ± 29.4 (range, 12-115) months. The mean age of the patients was 16.4 ± 0.7 (range, 15-17) years. The Knee injury and Osteoarthritis Outcome Score (KOOS) and International Knee Document Committee (IKDC) increased of + 41.9/100 (P = 0.003) and + 33.2/100 (P = < 0.0001) points, respectively. The Lysholm Knee Score improved of + 20.6/100 (P = 0.02) points. The Visual Analogue Scale (VAS) for pain reduced of - 3.6/10 (P = 0.004) points. The Tegner scale did not show any statistically significant improvement from baseline to follow-up (P = n.s.). The rate of graft hypertrophy was 12.5% (5 of 40 patients), and the rate of failure 5.6% (8 of 142 patients). CONCLUSION: ACI for chondral defects of the knee is effective to improve PROMs in skeletally immature patients. The safety profile of ACI still remains controversial. LEVEL OF EVIDENCE: III.

Novel Fluoroquinolones with Possible Antibacterial Activity in Gram-Negative Resistant Pathogens: In Silico Drug Discovery.

Antibiotic resistance is a global threat to public health, and the search for new antibacterial therapies is a current research priority. The aim of this in silico study was to test nine new fluoroquinolones previously designed with potential leishmanicidal activity against Campylobacter jejuni, Escherichia coli, Neisseria gonorrhoeae, Pseudomonas aeruginosa, and Salmonella typhi, all of which are considered by the World Health Organization to resistant pathogens of global concern, through molecular docking and molecular dynamics (MD) simulations using wild-type (WT) and mutant-type (MT) DNA gyrases as biological targets. Our results showed that compound 9FQ had the best binding energy with the active site of E. coli in both molecular docking and molecular dynamics simulations. Compound 9FQ interacted with residues of quinolone resistance-determining region (QRDR) in GyrA and GyrB chains, which are important to enzyme activity and through which it could block DNA replication. In addition to compound 9FQ, compound 1FQ also showed a good affinity for DNA gyrase. Thus, these newly designed molecules could have antibacterial activity against Gram-negative microorganisms. These findings represent a promising starting point for further investigation through in vitro assays, which can validate the hypothesis and potentially facilitate the development of novel antibiotic drugs.

Angiogenic and molecular diversity determine hepatic melanoma metastasis and response to anti-angiogenic treatment.

BACKGROUND: Cutaneous melanoma exhibits heterogeneous metastatic patterns and prognosis. In this regard, liver metastasis, which is detected in ~ 10-20% of stage 4 patients, came to the fore of melanoma research, as it recently evolved as decisive indicator of treatment resistance to immune checkpoint inhibition. METHODS: Hepatic metastases were induced by intrasplenic injection of five different murine melanoma cell lines. The efficiencies of hepatic colonization, morphologic patterns, gene expression profiles and degree of vascularization were analyzed and Sorafenib was applied as anti-angiogenic treatment. RESULTS: WT31 melanoma showed the highest efficiency of hepatic colonization, while intermediate efficiencies were observed for B16F10 and RET, and low efficiencies for D4M and HCmel12. RNAseq-based gene expression profiles of high and intermediate metastatic melanomas in comparison to low metastatic melanomas indicated that this efficiency predominantly associates with gene clusters involved in cell migration and angiogenesis. Indeed, heterogeneous vascularization patterns were found in the five models. Although the degree of vascularization of WT31 and B16F10 metastases differed, both showed a strong response to Sorafenib with a successful abrogation of the vascularization. CONCLUSION: Our data indicate that molecular heterogeneity of melanomas can be associated with phenotypic and prognostic features of hepatic metastasis paving the way for organ-specific anti-angiogenic therapeutic approaches.

Caspase-8 promotes c-Rel-dependent inflammatory cytokine expression and resistance against Toxoplasma gondii.

Caspase-8 is a key integrator of cell survival and cell death decisions during infection and inflammation. Following engagement of tumor necrosis factor superfamily receptors or certain Toll-like receptors (TLRs), caspase-8 initiates cell-extrinsic apoptosis while inhibiting RIPK3-dependent programmed necrosis. In addition, caspase-8 has an important, albeit less well understood, role in cell-intrinsic inflammatory gene expression. Macrophages lacking caspase-8 or the adaptor FADD have defective inflammatory cytokine expression and inflammasome priming in response to bacterial infection or TLR stimulation. How caspase-8 regulates cytokine gene expression, and whether caspase-8-mediated gene regulation has a physiological role during infection, remain poorly defined. Here we demonstrate that both caspase-8 enzymatic activity and scaffolding functions contribute to inflammatory cytokine gene expression. Caspase-8 enzymatic activity was necessary for maximal expression of Il1b and Il12b, but caspase-8 deficient cells exhibited a further decrease in expression of these genes. Furthermore, the ability of TLR stimuli to induce optimal IκB kinase phosphorylation and nuclear translocation of the nuclear factor kappa light chain enhancer of activated B cells family member c-Rel required caspase activity. Interestingly, overexpression of c-Rel was sufficient to restore expression of IL-12 and IL-1ß in caspase-8-deficient cells. Moreover, Ripk3-/-Casp8-/- mice were unable to control infection by the intracellular parasite Toxoplasma gondii, which corresponded to defects in monocyte recruitment to the peritoneal cavity, and exogenous IL-12 restored monocyte recruitment and protection of caspase-8-deficient mice during acute toxoplasmosis. These findings provide insight into how caspase-8 controls inflammatory gene expression and identify a critical role for caspase-8 in host defense against eukaryotic pathogens.

Chiral Phosphoric Acid Catalyzed Conversion of Epoxides into Thiiranes: Mechanism, Stereochemical Model, and New Catalyst Design.

Computations and experiments leading to new chiral phosphoric acids (CPAs) for epoxide thionations are reported. Density functional theory calculations reveal the mechanism and origin of the enantioselectivity of such CPA-catalyzed epoxide thionations. The calculated mechanistic information was used to design new efficient CPAs that were tested experimentally and found to be highly effective. Bulky ortho-substituents on the 3,3'-aryl groups of the CPA are important to restrict the position of the epoxide in the key transition states for the enantioselectivity-determining step. Larger para-substituents significantly improve the enantioselectivity of the reaction.

Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling.

BACKGROUND & AIMS: Angiocrine signaling by liver sinusoidal endothelial cells (LSECs) regulates hepatic functions such as growth, metabolic maturation, and regeneration. Recently, we identified GATA4 as the master regulator of LSEC specification during development. Herein, we studied the role of endothelial GATA4 in the adult liver and in hepatic pathogenesis. METHODS: We generated adult Clec4g-icretg/0xGata4fl/fl (Gata4LSEC-KO) mice with LSEC-specific depletion of Gata4. Livers were analyzed by histology, electron microscopy, immunohistochemistry/immunofluorescence, in situ hybridization, and LSECs were isolated for gene expression profiling, ChIP- and ATAC-sequencing. Partial hepatectomy was performed to assess regeneration. We used choline-deficient, l-amino acid-defined (CDAA) diet and chronic carbon tetrachloride exposure to model liver fibrosis. Human single cell RNA-seq data sets were analyzed for endothelial alterations in healthy and cirrhotic livers. RESULTS: Genetic Gata4 deficiency in LSECs of adult mice caused perisinusoidal liver fibrosis, hepatopathy and impaired liver regeneration. Sinusoidal capillarization and LSEC-to-continuous endothelial transdifferentiation were accompanied by a profibrotic angiocrine switch involving de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. Increased chromatin accessibility and amplification by activated MYC mediated angiocrine Pdgfb expression. As observed in Gata4LSEC-KO livers, CDAA diet-induced perisinusoidal liver fibrosis was associated with GATA4 repression, MYC activation and a profibrotic angiocrine switch in LSECs. Comparison of CDAA-fed Gata4LSEC-KO and control mice demonstrated that endothelial GATA4 indeed protects against dietary-induced perisinusoidal liver fibrosis. In human cirrhotic livers, GATA4-positive LSECs and endothelial GATA4 target genes were reduced, while non-LSEC endothelial cells and MYC target genes including PDGFB were enriched. CONCLUSIONS: Endothelial GATA4 protects against perisinusoidal liver fibrosis by repressing MYC activation and profibrotic angiocrine signaling at the chromatin level. Therapies targeting the GATA4/MYC/PDGFB/PDGFRß axis offer a promising strategy for prevention and treatment of liver fibrosis. LAY SUMMARY: The liver vasculature is supposed to play a major role in the development of liver fibrosis and cirrhosis, which can lead to liver failure and liver cancer. Herein, we discovered that structural and transcriptional changes induced by genetic deletion of the transcription factor GATA4 in the hepatic endothelium were sufficient to cause liver fibrosis. Activation of the transcription factor MYC and de novo expression of the "angiocrine" growth factor PDGFB were identified as downstream drivers of fibrosis and as potential therapeutic targets for this potentially fatal disease.

Cell-Intrinsic Wnt4 Influences Conventional Dendritic Cell Fate Determination to Suppress Type 2 Immunity.

Whether conventional dendritic cells (cDC) acquire subset identity under direction of Wnt family glycoproteins is unknown. We demonstrate that Wnt4, a ß-catenin-independent Wnt ligand, is produced by both hematopoietic and nonhematopoietic cells and is both necessary and sufficient for preconventional DC1/cDC1 maintenance. Whereas bone marrow cDC precursors undergo phosphoJNK/c-Jun activation upon Wnt4 treatment, loss of cDC Wnt4 in CD11cCreWnt4flox/flox mice impaired differentiation of CD24+, Clec9A+, CD103+ cDC1 compared with CD11cCre controls. Conversely, single-cell RNA sequencing analysis of bone marrow revealed a 2-fold increase in cDC2 gene signature genes, and flow cytometry demonstrated increased numbers of SIRP-α+ cDC2 amid lack of Wnt4. Increased cDC2 numbers due to CD11c-restricted Wnt4 deficiency increased IL-5 production, group 2 innate lymphoid cell expansion, and host resistance to the hookworm parasite Nippostrongylus brasiliensis Collectively, these data uncover a novel and unexpected role for Wnt4 in cDC subset differentiation and type 2 immunity.

Quantitative historical analysis uncovers a single dimension of complexity that structures global variation in human social organization.

Do human societies from around the world exhibit similarities in the way that they are structured, and show commonalities in the ways that they have evolved? These are long-standing questions that have proven difficult to answer. To test between competing hypotheses, we constructed a massive repository of historical and archaeological information known as "Seshat: Global History Databank." We systematically coded data on 414 societies from 30 regions around the world spanning the last 10,000 years. We were able to capture information on 51 variables reflecting nine characteristics of human societies, such as social scale, economy, features of governance, and information systems. Our analyses revealed that these different characteristics show strong relationships with each other and that a single principal component captures around three-quarters of the observed variation. Furthermore, we found that different characteristics of social complexity are highly predictable across different world regions. These results suggest that key aspects of social organization are functionally related and do indeed coevolve in predictable ways. Our findings highlight the power of the sciences and humanities working together to rigorously test hypotheses about general rules that may have shaped human history.

The quadriceps insertion of the medial patellofemoral complex demonstrates the greatest anisometry through flexion.

PURPOSE: A comprehensive understanding of the biomechanical properties of the medial patellofemoral complex (MPFC) is necessary when performing an MPFC reconstruction. How components of the MPFC change over the course of flexion can influence the surgeon's choice of location for graft fixation along the extensor mechanism. The purpose of this study was to (1) determine native MPFC length changes throughout a 90° arc using an anatomically based attachment and using Schöttle's point, and (2) compare native MPFC length changes with different MPFC attachment sites along the extensor mechanism. METHODS: Eight fresh-frozen (n = 8), cadaveric knees were dissected of all soft tissue structures except the MPFC. The distance between the femoral footprint (identified through anatomical landmarks and Schottle's point) and the MPFC was calculated at four attachment sites along the extensor mechanism [midpoint of the patella [MP], the center of the osseous footprint of the MPFC (FC), the superomedial corner of the patella at the quadriceps insertion (SM), and the proximal extent of the MPFC along the quadriceps tendon (QT)] at 0°, 20°, 40°, 60°, and 90° of flexion. RESULTS: Length changes were investigated between the MPFL femoral attachment site and the radiographic surrogate of the MPFL attachment site, Schottle's Point (SP). Paired t tests at each of the four components showed no differences in length change from 0° to 90° when comparing SP to the anatomic MPFC insertion. MPFL length changes from 0° to 90° were greatest at the QT point (13.9 ± 3.0 mm) and smallest at the MP point (2.7 ± 4.4 mm). The FC and SM points had a length change of 6.6 ± 4.2 and 9.0 ± 3.8, respectively. Finally, when examining how the length of the MPFC components changed through flexion, the greatest differences were seen at QT where all comparisons were significant (p < 0.01) except when comparing 0° vs 20° (n.s.). CONCLUSION: The MPFC demonstrates the most significant length changes between 0° and 20° of flexion, while more isometric behavior was seen during 20°-90°. The attachment points along the extensor mechanism demonstrate different length behaviors, where the more proximal components of the MPFC display greater anisometry through the arc of motion. When performing a proximal MPFC reconstruction, surgeons should expect increased length changes compared to reconstructions utilizing distal attachment sites.

[Arthroscopically assisted transmalleolar internal fixation of a lateral osteochondral lesion of the talus]. / Arthroskopisch gestützte, transmalleolare interne Fixation einer lateralen osteochondralen Läsion des Talus.

Osteochondral lesions (OCL) of the talus can be caused by isolated or recurrent traumatic events. The established surgical treatment techniques are predominantly based on defect coverage by stimulation of fibrous cartilage or transplantation of osteochondral tissue or chondrocytes. An alternative is the preservation of an intact autochthonous hyaline cartilage surface with reconstruction of the subchondral lamella and the natural joint congruence. This anatomical technique can be used for selected acute and chronic OCL and can frequently be carried out arthroscopically. This article presents the indications, contraindications, advantages and targets as well as the planning and execution of arthroscopically assisted transmalleolar internal fixation of a lateral OCL of the talus.

[Osteochondral lesions of the talus : Individualized approach based on established and innovative reconstruction techniques]. / Osteochondrale Läsionen des Talus : Individualisiertes Vorgehen mithilfe etablierter und innovativer Rekonstruktionsverfahren.

Osteochondral lesions (OCL) of the talus are defined as chondral damage with subchondral involvement. The traumatic etiology is important; in particular, sprains and fractures can lead to lesions of the articular surface and the subchondral plate. As a result, unstable lesions and subchondral cysts can trigger substantial persistent pain and functional impairments. A primary conservative treatment can be considered and is especially recommended in children and adolescents; however, return to previous sports activity and level is often not achieved. The principles of reconstructive surgical management include internal fixation of osteochondral fragments, bone marrow stimulation, autologous membrane-augmented chondrogenesis ± bone grafting, osteochondral transfer, retrograde techniques ± bone grafting, (matrix-associated) autologous chondrocyte implantation and autologous osteoperiosteal graft from the iliac crest. Additional surgical procedures for ankle stabilization and deformity correction should be considered if necessary.

Topographic Analysis of Lateral Versus Medial Femoral Condyle Donor Sites for Oblong Medial Femoral Condyle Lesions.

PURPOSE: To analyze the topographic matching of oblong osteochondral allografts to treat large oval medial femoral condyle (MFC) lesions using computer simulation models. The secondary objective was to determine whether lateral femoral condyle (LFC) grafts would have a similar surface matching when compared with MFC grafts in this setting. METHODS: Human femoral hemicondyles (10 MFCs, 7 LFCs) underwent 3-dimensional computed tomography. Models were created from computed tomography images and exported into point-cloud models. Donor-recipient matches with large condylar width mismatch were excluded. The remaining specimen were divided into 3 donor-recipient groups with 2 defect sizes (17 × 30 mm and 20 × 30 mm): 20 MFC donor (MFCd)-MFC recipient (MFCr), 27 ipsilateral LFC donor (LFCd)-MFCr, and 26 contralateral LFCd-MFCr. Grafts were optimally virtually aligned with the MFCr defect. Mismatch of the articular cartilage and subchondral bone surfaces between the graft and the defect and articular step-off were calculated. RESULTS: MFCd grafts resulted in articular cartilage surface mismatch and peripheral step of less than 0.5 mm for both defect sizes. The subchondral bone surface mismatch was significantly greater than the articular cartilage surface mismatch (P < .01) in both defect sizes). Conversely, the ipsilateral and contralateral LFCd grafts resulted in significantly greater articular cartilage surface mismatch and step-off for both defect sizes when compared to MFCd grafts (P < .01). CONCLUSIONS: Oblong MFC allografts provide acceptable topographic matching for large oval MFC lesions when condylar width differences are minimized. However, concern exists in using oblong LFC allografts for MFC defects, as this can result in increased peripheral step-off and surface mismatch. CLINICAL RELEVANCE: These data reinforce the ability to use oblong MFC osteochondral allograft for treating oval cartilage lesions of the MFC when condylar width is considered. Although other studies have demonstrated LFCs can be used to treat circular defects on the MFC, this may not be true for oblong grafts.

Return to Sport and Patient Satisfaction After Meniscal Allograft Transplantation.

PURPOSE: To investigate patient return to sport and satisfaction after meniscal allograft transplantation (MAT). METHODS: Patients undergoing MAT using a bone bridge technique between 2013 and 2015 with minimum 2-year follow-up were retrospectively reviewed. They completed a survey regarding return to sport, satisfaction, and subsequent surgery in addition to patient-reported outcome measures. RESULTS: Of 117 patients, 87 (74.4%) were available at an average follow-up of 3.64 years (range, 2.01-5.13 years). The mean age at the time of surgery was 28.99 ± 8.26 years. Lateral MAT was performed in 44 cases (50.6%); medial MAT, 42 (48.3%); and combined medial and lateral MAT, 1 (1.1%). Concomitant procedures were performed in 72 patients (82.7%) including cartilage restoration (n = 65, 74.7%), realignment (n = 9, 10.3%), and anterior cruciate ligament reconstruction (n = 9, 10.3%). Patients experienced significant improvement in the Lysholm score (P < .001), International Knee Documentation Committee score (P < .001), Knee Injury and Osteoarthritis Outcome Score (KOOS)-Quality of Life (P < .001), KOOS-Activities of Daily Living (ADL) (P < .001), KOOS-Pain (P < .001), KOOS-Sports (P = .001), KOOS-Symptoms (P = .003), Short Form 12 physical score (P < .001), and Veterans Rand-12 physical score (P < .001). Reoperation was performed in 26 patients (29.9%); failure occurred in 12 patients (13.8%; total knee arthroplasty in 1, unicompartmental arthroplasty in 2, and total meniscectomy in 9). Overall, 77.0% of patients were satisfied with their outcome. Prior to MAT, 82 patients (94.3%) participated in sporting activities; 62 patients (75.6%) returned to at least one sport at 12.58 ± 6.20 months postoperatively, with 30 (48.4%) reaching their preoperative level of intensity and 72 (87.8%) discontinuing at least one of their preoperative sports. The most common reasons for sports discontinuation postoperatively were prevention of further damage (73.6%), pain with activity (51.4%), fear of further injury (48.6%), surgeon recommendation (33.3%), and swelling with activity (30.6%). Patients were satisfied with their sports participation at a rate of 62.1%. CONCLUSIONS: In a complex patient population undergoing arthroscopic MAT, 75.6% of patients were able to return to at least one sport at an average of 12.58 ± 6.20 months postoperatively. The level of sport declined, with 93.5% of patients restricting involvement to recreational sports after MAT and 48.4% returning to their preoperative level of activity intensity. In addition, 87.8% of patients reported discontinuing a sport in which they had participated preoperatively. The most common reasons for decreasing level of sport were prevention of further damage, pain or swelling with sports, and fear of further injury. The reoperation rate after MAT was 29.9%. Most patients were satisfied with the outcome of surgery, with 77.0% satisfied in general and 62.1% satisfied with their ability to play sports. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Differential Contributions of the Quadriceps and Patellar Attachments of the Proximal Medial Patellar Restraints to Resisting Lateral Patellar Translation.

PURPOSE: To define the contributions of the of the medial patellofemoral ligament (MPFL) and medial quadriceps tendon femoral ligament (MQTFL) to lateral patellar translation as the knee moves through a 90° arc of motion. METHODS: Six pairs of bilateral cadaveric knee specimens (12 knees) were dissected and potted in perfect lateral position using fluoroscopy. An eye screw was placed in the midpoint on the lateral aspect of the patella. Each knee underwent testing in 4 conditions after sequential sectioning: intact, lateral retinacular release, randomized MQTFL or MPFL sectioning, and complete proximal medial patellar restraint (PMPR) sectioning. With a custom machined jig, all knees were tested at 0, 10, 20, 30, 45, 60, and 90° of flexion on an MTS machine with 20N of lateral patellar force applied and displacement recorded. RESULTS: PMPR extensor mechanism insertion on all specimens was identified 50% on the quadriceps tendon and 50% on the proximal aspect of the medial patella. Isolated MPFL sectioning resulted in significantly increased lateral displacement compared to the lateral release state at all flexion angles tested except 0°. There was significantly increased lateral patellar displacement with complete sectioning compared with isolated proximal sectioning at all degrees of knee flexion except 0°. However, complete sectioning following isolated MPFL sectioning did not demonstrate significance at any angle. CONCLUSIONS: Compared with the MQTFL, the MPFL is primarily responsible for resistance to lateral patellar translation throughout a 0° to 90° arc of motion. The MPFL provides a similar resistance to lateral patellar displacement as the fully intact PMPR; however, the MQTFL may contribute to resistance in full extension. CLINICAL SIGNIFICANCE: Proximal medial patellar restraint reconstruction techniques involving both the patellar and quadriceps insertion have been described; however, the unique contributions of the native anatomy to lateral patellar restraint have not been investigated.