Recurrent Loss-of-Function Mutations Reveal Costs to OAS1 Antiviral Activity in Primates.

Immune responses counteract infections but also cause collateral damage to hosts. Oligoadenylate synthetase 1 (OAS1) binds double-stranded RNA from invading viruses and produces 2'-5' linked oligoadenylate (2-5A) to activate ribonuclease L (RNase L), which cleaves RNA to inhibit virus replication. OAS1 can also undergo autoactivation by host RNAs, a potential trade-off to antiviral activity. We investigated functional variation in primate OAS1 as a model for how immune pathways evolve to mitigate costs and observed a surprising frequency of loss-of-function variation. In gorillas, we identified a polymorphism that severely decreases catalytic function, mirroring a common variant in humans that impairs 2-5A synthesis through alternative splicing. OAS1 loss-of-function variation is also common in monkeys, including complete loss of 2-5A synthesis in tamarins. The frequency of loss-of-function alleles suggests that costs associated with OAS1 activation can be so detrimental to host fitness that pathogen-protective effects are repeatedly forfeited.

Patient-Specific Parameters Associated With Traction in Primary and Revision Hip Arthroscopic Surgery.

BACKGROUND: Distraction of the hip joint is a necessary step during hip arthroscopic surgery. The force of traction needed to distract the hip is not routinely measured, and little is known about which patient factors may influence this force. PURPOSE: To quantify the force of traction required for adequate distraction of the hip during arthroscopic surgery and explore the relationship between hip joint stiffness and patient-specific demographics, flexibility, and anatomy. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 101 patients (61 female) undergoing primary hip arthroscopic surgery were prospectively enrolled. A load cell attached to the traction boot continuously measured traction force. Fluoroscopic images were obtained before and after traction to measure joint displacement. The stiffness coefficient was calculated as the force of traction divided by joint displacement. Relationships between the stiffness coefficient and patient demographics and clinical parameters were investigated using a univariable regression model. The regression analysis was repeated separately by patient sex. Variables significant at P < .05 were included in a multivariable regression model. RESULTS: The instantaneous peak force averaged 80 ± 18 kilogram-force (kgf), after which the force required to maintain distraction decreased to 57 ± 13 kgf. In univariable regression analysis, patient sex, alpha angle, hamstring flexibility, and Beighton hypermobility score were each correlated to stiffness. However, patient sex was the only significant variable in the multivariable regression model. Intrasex analysis demonstrated that increased hamstring flexibility correlated with decreased final holding stiffness in male patients and that higher Beighton scores correlated with decreased maximal stiffness in female patients. CONCLUSION: Male patients undergoing primary arthroscopic surgery have greater stiffness to hip distraction during arthroscopic surgery compared with female patients. In male patients, stiffness increased with decreasing hamstring flexibility. In female patients, increased Beighton scores corresponded to decreased stiffness. The presence of a labral tear was not correlated with stiffness to distraction. These data may be used to identify patients in whom a specific focus on capsular repair and/or plication may be warranted.

Distal Femoral Osteotomy for the Valgus Knee: Medial Closing Wedge Versus Lateral Opening Wedge: A Systematic Review.

PURPOSE: (1) To determine the radiographic correction/healing rate, patient-reported outcomes, reoperation rate, and complication rate after distal femoral osteotomy (DFO) for the valgus knee with lateral compartment pathology. (2) To summarize the reported results of medial closing wedge and lateral opening wedge DFO. METHODS: We conducted a systematic review of PubMed, MEDLINE, and CINAHL to identify studies reporting outcomes of DFOs for the valgus knee. Keywords included "distal femoral osteotomy," "chondral," "cartilage," "valgus," "joint restoration," "joint preservation," "arthritis," and "gonarthrosis." Two authors first reviewed the articles; our study exclusion criteria were then applied, and the articles were included on the basis relevance defined by the aforementioned criteria. The Methodological Index for Nonrandomized Studies scale judged the quality of the literature. Sixteen studies were relevant to the research questions out of 191 studies identified by the original search. RESULTS: Sixteen studies were identified reporting on 372 osteotomies with mean follow-up of 45 to 180 months. All studies reported mean radiographic correction to a near neutral mechanical axis, with 3.2% nonunion and 3.8% delayed union rates. There was a 9% complication rate and a 34% reoperation rate, of which 15% were converted to arthroplasty. There were similar results reported for medial closing wedge and lateral opening wedge techniques, with a higher conversion to arthroplasty in the medial closing wedge that was confounded by longer mean follow-up in this group (mean follow-up 100 v 58 months). CONCLUSIONS: DFOs for the valgus knee with lateral compartment disease provide improvements in patient-reported knee health-related quality of life at midterm follow-up but have high rates of reoperation. No evidence exists proving better results of either the lateral opening wedge or medial closing wedge techniques. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.

Failures and Reoperations After Matrix-Assisted Cartilage Repair of the Knee: A Systematic Review.

PURPOSE: To quantify the reported failures and reoperations for the emerging technique of matrix-assisted cartilage repair at short-term and midterm follow-up. METHODS: We conducted a systematic review of 3 databases from March 2004 to February 2014 using keywords important for articular cartilage repair. Two authors reviewed the articles, the study exclusion criteria were applied, and articles were determined to be relevant (or not) to the research question. All studies with a minimum of 2 years' clinical follow-up were reviewed for all reported reoperations. The reasons for reoperations were recorded. RESULTS: We reviewed 66 articles from the 301 articles identified in the original systematic search. There were 60 articles on matrix-assisted cartilage transplantation and 6 articles on matrix-induced chondrogenesis. The matrix-assisted cartilage transplantation studies reported on a total of 1,380 patients at 2 to 5 years' follow-up. Among these, there were 72 reoperations (5%) including 46 treatment failures (3%). These numbers increased to an 11% reoperation rate and 9% treatment failure rate at minimum 5-year follow-up of 961 patients. The most common procedures performed other than revision cartilage surgery or arthroplasty were manipulation under anesthesia for arthrofibrosis (0.7%) and debridement for graft hypertrophy (1.2%). The matrix-induced chondrogenesis studies reported on 163 patients. Among these, there were 15 reoperations (9%) that included 4 treatment failures (2%), 9 manipulations under anesthesia (6%), and 2 debridements for graft hypertrophy (1%). CONCLUSIONS: Treatment failure rates for matrix-assisted cartilage repair increase from short-term to midterm follow-up, with 11% of patients having undergone further surgery at a minimum of 5 years' follow-up. These data can be used to counsel patients on the potential need for further operative intervention after this emerging cartilage repair technique.

Overlapping Patterns of Rapid Evolution in the Nucleic Acid Sensors cGAS and OAS1 Suggest a Common Mechanism of Pathogen Antagonism and Escape.

A diverse subset of pattern recognition receptors (PRRs) detects pathogen-associated nucleic acids to initiate crucial innate immune responses in host organisms. Reflecting their importance for host defense, pathogens encode various countermeasures to evade or inhibit these immune effectors. PRRs directly engaged by pathogen inhibitors often evolve under recurrent bouts of positive selection that have been described as molecular 'arms races.' Cyclic GMP-AMP synthase (cGAS) was recently identified as a key PRR. Upon binding cytoplasmic double-stranded DNA (dsDNA) from various viruses, cGAS generates the small nucleotide secondary messenger cGAMP to signal activation of innate defenses. Here we report an evolutionary history of cGAS with recurrent positive selection in the primate lineage. Recent studies indicate a high degree of structural similarity between cGAS and 2'-5'-oligoadenylate synthase 1 (OAS1), a PRR that detects double-stranded RNA (dsRNA), despite low sequence identity between the respective genes. We present comprehensive comparative evolutionary analysis of cGAS and OAS1 primate sequences and observe positive selection at nucleic acid binding interfaces and distributed throughout both genes. Our data revealed homologous regions with strong signatures of positive selection, suggesting common mechanisms employed by unknown pathogen encoded inhibitors and similar modes of evasion from antagonism. Our analysis of cGAS diversification also identified alternately spliced forms missing multiple sites under positive selection. Further analysis of selection on the OAS family in primates, which comprises OAS1, OAS2, OAS3 and OASL, suggests a hypothesis where gene duplications and domain fusion events result in paralogs that provide another means of escaping pathogen inhibitors. Together our comparative evolutionary analysis of cGAS and OAS provides new insights into distinct mechanisms by which key molecular sentinels of the innate immune system have adapted to circumvent viral-encoded inhibitors.

What is the effect of matrices on cartilage repair? A systematic review.

BACKGROUND: Articular cartilage has minimal endogenous ability to undergo repair. Multiple chondral restoration strategies have been attempted with varied results. QUESTIONS/PURPOSES: The purpose of our review was to determine: (1) Does articular chondrocyte transplantation or matrix-assisted articular chondrocyte transplantation provide better patient-reported outcomes scores, MRI morphologic measurements, or histologic quality of repair tissue compared with microfracture in prospective comparative studies of articular cartilage repair; and (2) which available matrices for matrix-assisted articular chondrocyte transplantation show the best patient-reported outcomes scores, MRI morphologic measurements, or histologic quality of repair tissue? METHODS: We conducted a systematic review of PubMed, CINAHL, and MEDLINE from March 2004 to February 2014 using keywords determined to be important for articular cartilage repair, including "cartilage", "chondral", "cell source", "chondrocyte", "matrix", "augment", "articular", "joint", "repair", "treatment", "regeneration", and "restoration" to find articles related to cell-based articular cartilage repair of the knee. The articles were reviewed by two authors (JDW, MKH), our study exclusion criteria were applied, and articles were determined to be relevant (or not) to the research questions. The Methodological Index for Nonrandomized Studies (MINORS) scale was used to judge the quality of nonrandomized manuscripts used in this review and the Jadad score was used to judge the quality of randomized trials. Seventeen articles were reviewed for the first research question and 83 articles were reviewed in the second research question from 301 articles identified in the original systematic search. The average MINORS score was 9.9 (62%) for noncomparative studies and 16.1 (67%) for comparative studies. The average Jadad score was 2.3 for the randomized studies. RESULTS: Articular chondrocyte transplantation shows better patient-reported outcomes at 5 years in patients without chronic symptoms preoperatively compared with microfracture (p = 0.026). Matrix-assisted articular chondrocyte transplantation consistently showed improved patient-reported functional outcomes compared with microfracture (p values ranging from < 0.001 to 0.029). Hyalograft C(®) (Anika Therapeutics Inc, Bedford, MA, USA) and Chondro-gide(®) (Genzyme Biosurgery, Kastrup, Denmark) are the matrices with the most published evidence in the literature, but no studies comparing different matrices met our inclusion criteria, because the literature consists only of uncontrolled case series. CONCLUSIONS: Matrix-assisted articular chondrocyte transplantation leads to better patient-reported outcomes in cartilage repair compared with microfracture; however, future prospective research is needed comparing different matrices to determine which products optimize cartilage repair. LEVEL OF EVIDENCE: Level IV, therapeutic study.