Blood Flow Restriction Enhances Recovery After Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating neuromuscular and clinical outcomes of blood flow restriction (BFR) training after anterior cruciate ligament reconstruction (ACLR) compared to non-BFR rehabilitation protocols. METHODS: A systematic review was performed in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines by querying PubMed, MEDLINE, Scopus, the Cochrane Database for Systematic Review, and the Cochrane Central Register for Controlled Trials databases from inception through December 2023 to identify Level I-II RCTs evaluating outcomes of BFR training after ACLR compared to non-BFR rehabilitation. A meta-analysis was performed using random-effects models with standardized mean difference (SMD) for pain, muscle strength, and muscle volume, while mean difference (MD) was calculated for patient-reported outcome measures. RESULTS: Eight RCTs, consisting of 245 patients, met inclusion criteria, with 115 patients undergoing non-BFR rehabilitation versus 130 patients undergoing BFR after ACLR. Mean patient age was 27.2 ± 6.7 years, with the majority of patients being male (63.3%, n=138/218). The length of the BFR rehabilitation protocol was most commonly between 8-12 weeks (range, 14 days - 16 weeks). The majority of studies set the limb/arterial occlusion pressure in the BFR group at 80%. When compared to non-BFR rehabilitation, BFR resulted in significant improvement in isokinetic muscle strength (SMD: 0.77, p=0.02, I2: 58%), IKDC score (MD: 10.97, p=<.00001, I2: 77%), and pain (SMD: 1.52, p=.04, I2: 87%), but not quadriceps muscle volume (SMD: 0.28, p=0.43, I2: 76%). CONCLUSION: The use of BFR following ACLR led to improvements in pain, IKDC score and isokinetic muscle strength, with variable outcomes based on quadriceps strength, volume and thickness when compared to non-BFR rehabilitation.

Isolated, Proximal Tibiofibular Injuries in Athletic Patients: A Critical Analysis Review.

While infrequently reported, isolated injuries to the proximal tibiofibular (TF) joint primarily occur in young, athletic patients participating in sporting activities requiring explosive, high-impact movements, increasing the risk for potential twisting injuries, especially across a hyperflexed knee. The proximal TF joint is stabilized by bony, muscular and ligamentous structures, including both the anterior and posterior proximal TF complexes, with the anterior complex providing more robust stability. Proximal TF injuries frequently involve anterior and lateral displacement of the proximal fibula relative to its native articulation with the tibia. Proper diagnosis is dependent on careful and meticulous history and physical examination, as missed injuries are common, leading to the potential for continued pain, weakness and disability, especially in athletic patients. While spontaneous joint reduction has been reported, injuries may require formal closed reduction, with irreducible and chronic injuries requiring open reduction and stabilization, with recent investigations reporting satisfactory outcomes following anatomic reconstruction of the proximal TF ligament.

Most Anterior Cruciate Ligament Injuries in Professional Athletes Occur Without Contact to the Injured Knee: A Systematic Review of Video Analysis Studies.

PURPOSE: To systematically review studies using video analyses to evaluate anterior cruciate ligament (ACL) injury mechanisms in athletes during sport to better understand risk factors and the potential for injury prevention. METHODS: A literature search was conducted in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines statement using SCOPUS, PubMed, Medline, and the Cochrane Central Register for Controlled Trials from database inception through June 2023. Inclusion criteria included studies reporting on ACL injury mechanisms occurring in athletes based on video analysis. Athlete demographics, injury mechanisms, position of the lower extremity, and activity at the time of injury were recorded. RESULTS: A total of 13 studies, consisting of 542 athletes, met inclusion criteria. Most athletes competed at the professional level (91%, n = 495/542), with 79% (n = 422/536) of athletes being male. The most common sports were soccer (33%, n = 178/542) and American football (26%, n = 140/542). The most common injury mechanism was noncontact in 42.9% (n = 230/536) of athletes, followed by indirect contact (32.6%, n = 175/536) and direct contact (22.4%, n = 120/536). The most common position of injury was with a planted foot (91.7%, n = 110/120), full or near-full knee extension (84.4%, n = 49/58), and axial loading (81.3%, n = 87/107). Injuries commonly involved a deceleration/shift in momentum (50.4%, n = 123/244) or pivoting maneuver (36.1%, n = 77/213). At the time of injury, the knee commonly fell into valgus (76.8%, n = 225/293) with associated internal (53.5%, n = 46/86) or external tibiofemoral rotation (57.7%, n = 101/175). CONCLUSIONS: Most ACL injuries, when evaluated by video analysis, involve professional athletes participating in soccer and American football. The most common injury mechanism occurred without contact with the knee in extension during a deceleration or momentum shift, with resultant valgus and rotational force across the knee. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.

Degenerative Meniscus Tears Treated Nonoperatively With Platelet-Rich Plasma Yield Variable Clinical and Imaging Outcomes: A Systematic Review.

Purpose: To perform a systematic review on clinical and radiologic outcomes for meniscus tears treated nonoperatively with platelet-rich plasma (PRP). Methods: A literature search was performed according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using keywords and Boolean operators in SCOPUS, PubMed, Medline, and the Cochrane Central Register for Controlled Trials in April 2023. Inclusion criteria were limited to Level I to IV human studies reporting on outcomes of meniscus tears treated nonoperatively with PRP. Results: A total of 6 studies, consisting of 184 patients, were identified. There was 1 Level I study and 5 Level IV studies. Mean patient age was 47.8 ± 7.9 years, with 62% (n = 114/184) being female. The medial meniscus was treated in 95.7% (n = 157/164) of patients. Mean follow-up ranged from 75.9 days to 31.9 months. Meniscus tears were generally described as chronic, degenerative, or intrasubstance. In 4 studies, magnetic resonance imaging revealed variable improvement in meniscus grade with complete healing in 0% to 44% of patients and partial healing in 0% to 40% of patients. Four of 5 studies reported significant statistical improvement in pain from baseline to final follow-up. Studies reporting on clinical outcomes showed significant improvements Lysholm score (2 studies), Knee injury and Osteoarthritis Outcome Score total score (2 studies), and Tegner score (1 study). Successful return to sport occurred in 60% to 100% of patients. Two studies reported that most patients were either very satisfied or satisfied following treatment. Conclusions: The use of PRP injections for the treatment of meniscus tears led to variable results based on postoperative magnetic resonance evaluation and improvements in clinical outcomes, although the clinical significance remains unclear. The heterogeneity of PRP protocols, short-term follow-up, and lack of comparative studies limit findings. Level of Evidence: Level IV, systematic review of Level I to IV studies.

Comparing Clinical Outcomes and Knee Stability in Remnant- Preserving ACL Reconstruction Versus Standard ACL Reconstruction: A Systematic Review and Meta-analysis.

BACKGROUND: Anterior cruciate ligament reconstruction (ACLR) is one of the most frequently performed procedures in sports medicine, and undesirable outcomes still may range from 3-18%. One technique that has been explored to improve outcomes is preservation of the ACL remnant tibial stump, as opposed to stump debridement, at the time of reconstruction. PURPOSE: To review current high-level evidence and compare remnant-preserving anterior cruciate ligament reconstruction (ACLR) versus standard ACLR in terms of clinical outcomes and measures of knee stability. HYPOTHESIS: ACLR with remnant preservation would result in improved clinical outcomes and knee stability measures. STUDY DESIGN: Systematic review; Level of evidence, 2. METHODS: A systematic review of randomized controlled trials (RCTs) and cohort studies comparing remnant-preserving ACLR with standard ACLR with a minimum level of evidence of 2 was performed. Extracted data were summarized as general information, surgical characteristics, postoperative clinical outcomes, knee stability, graft evaluation, tunnel assessment, and postoperative complications. When feasible, a meta-analysis was performed. RESULTS: Seven RCTs and 5 cohort studies met the inclusion criteria. In total, 518 patients underwent remnant-preserving ACLR and 604 patients underwent standard ACLR. Ten studies performed the reconstruction with hamstring tendon (HT) autografts, 1 study with HT and bone-patellar tendon-bone autografts, and 1 study with HT and tibialis anterior allografts. On meta-analysis, remnant-preserving ACLR provided comparable outcomes with respect to International Knee Documentation Committee grades or Tegner scores. Even though there was a significant improvement in Lysholm scores (mean difference, -1.9; 95% CI, -2.89 to -0.91; P = .0002) with the remnant-preserving technique, this did not exceed previously reported minimal clinically important difference values. Remnant-preserving ACLR demonstrated superior knee stability in terms of patients achieving negative pivot shift when compared with the control group (88.89% vs 79.92%; P = .006). Although there was a significant improvement in the side-to-side difference in anterior tibial translation favoring remnant preservation (P = .004), the mean difference was 0.51 mm. CONCLUSION: Remnant-preserving ACLR, primarily with HT autografts, results in comparable clinical outcome scores and significantly improved knee stability relative to standard ACLR without remnant preservation without increasing the complication rate. Further studies will help clarify if remnant-preserving ACLR also has benefits in terms of enhancing graft integration and maturation, improving proprioception, limiting tunnel enlargement, and reducing complications.

Correlation between articular cartilage status on outcomes and survivorship following meniscal allograft transplantation: A systematic review.

PURPOSE: To conduct a systematic review evaluating potential correlations between preoperative articular cartilage integrity on outcomes and survivorship in patients undergoing meniscal allograft transplantation (MAT). METHODS: A literature search was performed by querying SCOPUS, PubMed, Medline, and the Cochrane Central Register for Controlled Trials from database inception through May 2023 according to the 2020 PRISMA statement. Inclusion criteria were limited to studies reporting on outcomes and survivorship following MAT based on preoperative cartilage status. RESULTS: Sixteen studies, consisting of 1723 patients (n = 1758 total menisci), were identified in six level III and 10 level IV evidence studies. There was high heterogeneity in cartilage grading scales, reporting of concomitant cartilage procedures, and indications for MAT based on osteoarthritis. Patients with lower limb malalignment were either excluded or corrected with an osteotomy. MAT failure rate was reported in nine studies, with four studies reporting a greater rate of failure in knees with higher degrees of cartilage damage. Eight studies reported on clinical outcomes based on cartilage grade, with two studies reporting significant differences in clinical outcomes based on cartilage grade. Of the five studies reporting management of full-thickness chondral defects with cartilage surgery, three studies reported no significant difference in survivorship based on preoperative cartilage grade, while one study reported lower survivorship and one study reported unclear results. No studies found significant differences in survivorship and outcomes between medial and lateral MAT. CONCLUSIONS: Conflicting results and high variability in reporting of concomitant cartilage repair and indications for MAT exist in studies evaluating the efficacy of MAT based on articular cartilage status. The degree of preoperative chondral damage did not have a strong relationship with clinical outcomes following MAT. Higher degrees of cartilage damage were associated with higher MAT failure rates, with possible improvement in survivorship when treated with an appropriate cartilage procedure. LEVEL OF EVIDENCE: Level IV.

Systematic Review and Meta-analysis of Clinical Outcomes After Management of Posterior Cruciate Ligament Tibial Avulsion Fractures.

Background: There is no consensus regarding the management of posterior cruciate ligament (PCL) avulsion fractures and the expected outcomes after treatment. Purpose: To systematically review clinical outcomes and complications after management of tibial-sided avulsion fractures of the PCL. Study Design: Systematic review; Level of evidence, 4. Methods: A literature search of Scopus, PubMed, Medline, and the Cochrane Central Register for Controlled Trials was performed in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Included were studies with evidence levels 1 to 4 that reported clinical outcomes after treatment of PCL tibial-sided avulsion fractures in humans. The quality of the included studies was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. A meta-analysis was performed for patient-reported outcome measures using random-effects modeling with 95% CIs. Results: A total of 58 studies published between 1999 and 2022 were identified. The mean MINORS score was 9.90 ± 4.12, indicating overall low-quality evidence with high risk of bias. The studies comprised 1440 patients (mean age, 32.59 ± 5.69 years; 75.2% males) with a mean follow-up of 26.9 ± 19.6 months (range, 5.3-126 months). Most patients were treated with open surgery (63.6%), followed by arthroscopic surgery (29.7%) and nonoperative treatment (6.7%). All patients reported significant posttreatment improvement in both subjective and objective outcomes (P < .05 for all). Arthroscopic surgery was associated with lower postoperative posterior tibial translation compared with open surgery (range, 0.6-3.2 vs 1.7-3.1 mm), greater preoperative to postoperative improvement in Lysholm score (54.6 vs 48.8; P < .0001), higher postoperative Tegner score (6.64 ± 1.03 vs 6.14 ± 2.29; P = .0448), and a higher rate of return to sport (100% vs 89.5%; P = .009). Nonoperative management was associated with a significantly lower fracture union rate (87% vs 99.1%; P < .0001) and greater postoperative side-to-side posterior translation (4.9 ± 4.3 mm) when compared with operative management. Conclusion: Although nonoperative and surgical management of PCL tibial avulsion fractures resulted in high rates of fracture union and improvement in functional outcome scores and a low incidence of complications, nonoperative treatment yielded a high side-to-side posterior displacement (>4 mm) with a lower rate of fracture union compared to surgical treatment.

Ulnar Collateral Ligament Internal Bracing Repair Technique for High-Grade Partial Proximal Tears in the Throwing Athlete.

The use of ulnar collateral ligament (UCL) repair with concomitant internal bracing for throwing athletes is a viable treatment option, but must take into account tear location, ligament quality, the expected length of the athlete's career, desire to advance to the next level of competition, and age. There has been increased interest in repair of UCL injuries in overhead athletes due to advancements in surgical technique, as well as improved technologies of anchor and suture material. In addition, return to sport can be accelerated compared to reconstruction. In this Technical Note, we demonstrate an ulnar collateral ligament repair technique, with internal bracing augmentation for high-grade partial proximal tears in the throwing athlete that is reliable, strong, and easily reproducible.

Radiofrequency-Based Chondroplasty Creates a Precise Area of Targeted Chondrocyte Death With Minimal Necrosis Outside the Target Zone: A Systematic Review.

Purpose: To systematically examine the effects of radiofrequency (RF) ablation or coblation (controlled ablation) on chondrocyte viability following knee chondroplasty in preclinical literature to determine the effectiveness and safety of RF-based techniques. Methods: A literature search was performed in September 2022 using PubMed and Scopus using the following search terms combined with Boolean operators: "chondroplasty," "radiofrequency," "thermal," "knee," "chondral defect," "articular cartilage," and "cartilage." The inclusion criteria consisted of preclinical studies examining the effect of RF ablation or coblation on chondrocytes during knee chondroplasty. Exclusion criteria consisted of studies reporting chondroplasty in joints other than the knee, clinical studies, in vitro studies using animal models, case reports, non-full-text articles, letters to editors, surveys, review articles, and abstracts. The following data were extracted from the included articles: author, year of publication, chondral defect location within the knee and chondral characteristics, RF probe characteristics, cartilage macroscopic description, microscopic chondrocyte description, and extracellular matrix characteristics. Results: A total of 17 articles, consisting of 811 cartilage specimens, were identified. The mean specimen age was 63.4 ± 6.0 (range, 37-89) years. Five studies used monopolar RF devices, 7 studies used bipolar RF devices, whereas 4 studies used both monopolar and bipolar RF devices. Time until cell death during ablation at any power was reported in 5 studies (n = 351 specimens), with a mean time to cell death of 54.4 seconds (mean range, 23.1-64) for bipolar RF and 56.3 seconds (mean range, 12.5-64) for monopolar RF devices. Chondrocyte cell death increased with increased wattage, while treatment time was positively correlated with deeper cell death. Conclusions: In this systematic review, histologic analysis demonstrated that RF-based chondroplasty creates a precise area of targeted chondrocyte death, with minimal evidence of necrosis outside the target zone. Caution must be exercised when performing RF-based chondroplasty due to the risk of cell death with increased application time and wattage. Clinical Relevance: Although RF ablation has demonstrated favorable results in preliminary trials, including smoother cartilage and less damage to the surrounding healthy tissue, the risks versus benefits of the procedure are largely unknown. Caution must be exercised when performing RF-based chondroplasty in the clinical setting due to the risk of cell death with increased application time and wattage.

Consistent Indications and Good Outcomes Despite High Variability in Techniques for Two-Stage Revision Anterior Cruciate Ligament Reconstruction: A Systematic Review.

PURPOSE: To systematically review the current literature regarding the indications, techniques, and outcomes after 2-stage revision anterior cruciate ligament reconstruction (ACLR). METHODS: A literature search was performed using SCOPUS, PubMed, Medline, and the Cochrane Central Register for Controlled Trials according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta Analyses statement. Inclusion criteria was limited to Level I-IV human studies reporting on indications, surgical techniques, imaging, and/or clinical outcomes of 2-stage revision ACLR. RESULTS: Thirteen studies with 355 patients treated with 2-stage revision ACLR were identified. The most commonly reported indications were tunnel malposition and tunnel widening, with knee instability being the most common symptomatic indication. Tunnel diameter threshold for 2-stage reconstruction ranged from 10 to 14 mm. The most common grafts used for primary ACLR were bone-patellar tendon-bone (BPTB) autograft, hamstring graft, and LARS (polyethylene terephthalate) synthetic graft. The time elapsed from primary ACLR to the first stage surgery ranged from 1.7 years to 9.7 years, whereas the time elapsed between the first and second stage ranged from 21 weeks to 13.6 months. Six different bone grafting options were reported, with the most common being iliac crest autograft, allograft bone dowels, and allograft bone chips. During definitive reconstruction, hamstring autograft and BPTB autograft were the most commonly used grafts. Studies reporting patient-reported outcome measures showed improvement from preoperative to postoperative levels in Lysholm, Tegner, and objective International Knee and Documentation Committee scores. CONCLUSIONS: Tunnel malpositioning and widening remain the most common indications for 2-stage revision ACLR. Bone grafting is commonly reported using iliac crest autograft and allograft bone chips and dowels, whereas hamstring autograft and BPTB autograft were the most used grafts during the second-stage definitive reconstruction. Studies showed improvements from preoperative to postoperative levels in commonly used patient reported outcomes measures. LEVEL OF EVIDENCE: Level IV, systematic review of Level I, III, and IV studies.

Return to Sport After Nonoperative Management of Elbow Ulnar Collateral Ligament Injuries: A Systematic Review and Meta-analysis.

BACKGROUND: Elbow ulnar collateral ligament (UCL) injuries can result in significant functional impairment in throwing and overhead athletes. UCL reconstruction and repair are proven treatments to restore stability, but the efficacy of nonoperative management is unclear. PURPOSE: To determine the rate of return to sports (RTS) and return to previous level of play (RTLP) in athletes sustaining medial elbow ulnar collateral ligament (UCL) injuries treated nonoperatively. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A literature search was performed using Scopus, PubMed, Medline, the Cochrane Database for Systematic Review, and the Cochrane Central Register for Controlled Trials according to the 2020 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Inclusion criteria were limited to level 1 to 4 human studies reporting on RTS outcomes after nonoperative management of UCL injuries. RESULTS: A total of 15 studies, consisting of 365 patients with a mean age of 20.45 ± 3.26 years, were identified. Treatment primarily consisted of platelet-rich plasma (PRP) injections with physical therapy (n = 189 patients; n = 7 studies) versus physical therapy alone (n = 176 patients; n = 8 studies). The overall RTS rate was 79.7% and the overall RTLP rate was 77.9%. Increasing UCL injury severity grade was associated with lower RTS rates. The RTS rate for proximal tears (89.7%; n = 61/68) was significantly greater than that for distal tears (41.2%; n = 14/34) (P < .0001). No significant difference in RTS rate was seen in patients treated with PRP versus those who did not receive PRP (P = .757). CONCLUSION: For athletes undergoing nonoperative management of UCL injuries, the overall RTS and RTLP rates were 79.7% and 77.9%, respectively, with excellent outcomes in grade 1 and grade 2 UCL injuries, specifically. The RTS rate for proximal tears was significantly higher than that for distal tears. Athletes were most commonly treated with PRP injection and physical therapy.

Complication Rates After Medial Patellofemoral Ligament Reconstruction Range From 0% to 32% With 0% to 11% Recurrent Instability: A Systematic Review.

PURPOSE: To review the incidence of complications following primary medial patellofemoral ligament (MPFL) reconstruction for recurrent patellar instability. METHODS: A literature search was conducted by querying PubMed and Scopus databases from database inception through August 2022 according to the 2020 Preferred Reporting Items for Systematic Review and Meta-analysis guidelines using the terms "Medial Patellofemoral Ligament," "MPFL," "reconstruction," "patellar," and "instability." Inclusion criteria included studies reporting complications following primary MPFL reconstruction for recurrent patellar instability. Exclusion criteria consisted of studies reporting on patients undergoing concurrent osteotomy procedures, revision reconstruction, and biomechanical or anatomic studies. The incidence of specific complications was aggregated from the included studies. RESULTS: Twenty-eight studies, consisting of 1,478 patients (n = 1521 knees), with a mean age of 23.3 years (mean range, 19-34.3 years) were identified. The overall incidence of complications ranged from 0% to 32.3% of knees. Failure ranged from 0% to 10.7% of knees, whereas patellar fractures occurred in 0% to 8.3% of knees, primarily in patients treated with full-length transverse tunnel or 2-tunnel techniques. All patellar fractures occurred in patients with patellar tunnels ranging from 4.5 to 6.0 mm in diameter. The incidence of postoperative knee stiffness/range of motion deficit ranged from 0% to 20%. Persistent anterior knee pain, ranged from 0% to 32.3%. CONCLUSIONS: Complications following primary MPFL reconstruction ranged from 0% to 32.3% of knees, primarily consisting of residual anterior knee pain. Failure ranged from 0% to 10.7% of knees, whereas patellar fractures were reported in 0% to 8.3% of knees. Fractures primarily occurred with a full-length transverse tunnel or 2-tunnel techniques, whereas all fractures occurred with patellar tunnels ranging from 4.5 mm to 6.0 mm in diameter. LEVEL OF EVIDENCE: IV; Systematic Review of Level I-IV studies.

Effects of Purinergic Receptor Deletion or Pharmacologic Modulation on Pulmonary Inflammation in Mice.

COVID-19 disease is associated with progressive accumulation of SARS-CoV-2-specific mRNA, which is recognized by innate immune receptors, such as TLR3. This in turn leads to dysregulated production of multiple cytokines, including IL-6, IFN-γ, CXCL1, and TNF-α. Excessive production of these cytokines leads to acute lung injury (ALI), which consequently compromises alveolar exchange of O2 and CO2. It is therefore of considerable interest to develop novel therapies that reduce pulmonary inflammation and stem production of pro-inflammatory cytokines, potentially for COVID-19 patients that are at high risk of developing severe disease. Purinergic signaling has a central role in fine-tuning the innate immune system, with P2 (nucleotide) receptor antagonists and adenosine receptor agonists having anti-inflammatory effects. Accordingly, we focused here on the potential role of purinergic receptors in driving neutrophilic inflammation and cytokine production in a mouse model of pulmonary inflammation. To mimic the effects of SARS-CoV-2-specific RNA accumulation in mice, we administered progressively increasing daily doses of a viral mimetic, polyinosinic:polycytidylic acid [poly(I:C)] into the airways of mice over the course of 1 week. Some mice also received increasing daily doses of ovalbumin to mimic virus-encoded protein accumulation. Animals receiving both poly(I:C) and ovalbumin displayed particularly high cytokine levels and neutrophilia, suggestive of both innate and antigen-specific, adaptive immune responses. The extent of these responses was diminished by genetic deletion (P2Y14R, P2X7R) or pharmacologic modulation (P2Y14R antagonists, A3AR agonists) of purinergic receptors. These results suggest that pharmacologic modulation of select purinergic receptors might be therapeutically useful in treating COVID-19 and other pulmonary infections.

Global variation in isolated posterior cruciate ligament reconstruction.

PURPOSE: In the setting of persistent instability or failed non-operative management, surgical reconstruction is commonly recommended for isolated posterior cruciate ligament (PCL) tears. The purpose of this study was to systematically review published studies to evaluate regional variation in the epidemiology of and surgical approaches to primary, isolated PCL reconstruction. METHODS: A systematic review was performed in June 2022 to identify studies examining operative techniques during primary, isolated PCL reconstruction. Collected variables consisted of reconstruction technique, graft type, graft source, tibial reconstruction technique, femoral and tibial drilling and fixation methods, and whether the remnant PCL was preserved or debrided. Studies were classified into four global regions: Asia, Europe, North America, and South America. RESULTS: Forty-five studies, consisting of 1461 total patients, were identified. Most of the included studies were from Asia (69%, n = 31/45). Single bundle reconstruction was more commonly reported in studies out of Asia, Europe, and North America. Hamstring autografts were utilized in 51.7% (n = 611/1181) of patients from Asia and 60.8% (n = 124/204) of patients from Europe. Trans-tibial drilling and outside-in femoral drilling were commonly reported in all global regions. The PCL remnant was generally debrided, while remnant preservation was commonly reported in studies from Asia. CONCLUSION: Surgical treatment of isolated PCL injuries varies by region, with the majority of published studies coming from Asia. Single-bundle reconstruction with hamstring autograft through a trans-tibial approach is the most commonly reported technique in the literature, with males reported to undergo isolated reconstruction more often than females. LEVEL OF EVIDENCE: Systematic review, Level IV.

Synthesis and pharmacological characterization of multiply substituted 2H-chromene derivatives as P2Y6 receptor antagonists.

P2Y6 receptor (P2Y6R) antagonists represent potential drugs for treating cancer, pain, neurodegeneration, asthma, diabetes, colitis and other disorders. However, there are few chemical classes of known competitive antagonists. We recently explored the structure activity relationship (SAR) of 2H-chromene derivatives as P2Y6R antagonists of moderate affinity. New analogues in this series modified at five positions were synthesized and shown to antagonize Ca2+ transients induced by the native agonist UDP in human (h) P2Y6R-expressing (but not turkey P2Y1R-, hP2Y2R- or hP2Y4R-expressing) astrocytoma cells. Alternatives to the reported 2-(trifluoromethyl)- and 3-nitro- substitutions of this scaffold were not identified. However, 6­fluoro 11 and 6­chloro 12 analogues displayed enhanced potency compared to other halogens, although still in the 1 - 2 µM range. Similar halogen substitution at 5, 7 or 8 positions reduced affinity. 5- or 8­Triethylsilylethynyl extension maintained hP2Y6R affinity, with IC50 0.46 µM for 26 (MRS4853). The 6,8­difluoro analogue 27 (IC50 2.99 µM) lacked off-target activities among 45 sites examined, unlike earlier analogues that bound to biogenic amine receptors. 11 displayed only one weak off-target activity (σ2). Mouse P2Y6R IC50s of 5, 25, 26 and 27 were 4.94, 17.6, 6.15 and 17.8 µM, respectively, but most other analogues had reduced affinity (>20 µM) compared to the hP2Y6R. These analogues are suitable for evaluation in in vivo inflammation and cancer models, which will be performed in the future studies.

Bridged Piperidine Analogues of a High Affinity Naphthalene-Based P2Y14R Antagonist.

High affinity phenyl-piperidine P2Y14R antagonist 1 (PPTN) was modified with piperidine bridging moieties to probe receptor affinity and hydrophobicity. Various 2-azanorbornane, nortropane, isonortropane, isoquinuclidine, and ring-opened cyclopentylamino derivatives preserved human P2Y14R affinity (fluorescence binding assay), and their pharmacophoric overlay was compared. Enantiomeric 2-azabicyclo[2.2.1]hept-5-en-3-one precursors assured stereochemically unambiguous, diverse products. Pure (S,S,S) 2-azanorbornane enantiomer 15 (MRS4738) displayed higher affinity than 1 (3-fold higher affinity than enantiomer 16) and in vivo antihyperallodynic and antiasthmatic activity. Its double prodrug 143 (MRS4815) dramatically reduced lung inflammation in a mouse asthma model. Related lactams 21-24 and dicarboxylate 42 displayed intermediate affinity and enhanced aqueous solubility. Isoquinuclidine 34 (IC50 15.6 nM) and isonortropanol 30 (IC50 21.3 nM) had lower lipophilicity than 1. In general, rigidified piperidine derivatives did not lower lipophilicity dramatically, except those rings with multiple polar groups. P2Y14R molecular modeling based on a P2Y12R structure showed stable and persistent key interactions for compound 15.

Structure-activity relationships of pyrimidine nucleotides containing a 5'-α,ß-methylene diphosphonate at the P2Y6 receptor.

The Gq-coupled P2Y6 receptor (P2Y6R) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2Y6R agonist and P2Y14R partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,ß-methylene bridge as P2Y6R agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5'-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2Y6R potency (MRS4554, 0.57 µM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2Y14R, respectively. However, 3-alkyl (31-33, 37, 38), ß-d-arabinofuranose (39) and 6-aza (40) substitution prevented P2Y6R activation. Thus, we have identified new α,ß-methylene bridged N4-extended CDP analogues as P2Y6R agonists that are highly selective over the P2Y14R.

Therapeutic Potential of Tuna Backbone Peptide and Its Analogs: An In Vitro and In Silico Study.

Tuna backbone peptide (TBP) has been reported to exert potent inhibitory activity against lipid peroxidation in vitro. Since this bears relevant physiological implications, this study was undertaken to assess the impact of peptide modifications on its bioactivity and other therapeutic potential using in vitro and in silico approach. Some TBP analogs, despite lower purity than the parent peptide, exerted promising antioxidant activities in vitro demonstrated by ABTS radical scavenging assay and cellular antioxidant activity assay. In silico digestion of the peptides resulted in the generation of antioxidant, angiotensin-converting enzyme (ACE), and dipeptidyl peptidase-IV (DPPIV) inhibitory dipeptides. Using bioinformatics platforms, we found five stable TBP analogs that hold therapeutic potential with their predicted multifunctionality, stability, non-toxicity, and low bitterness intensity. This work shows how screening and prospecting for bioactive peptides can be improved with the use of in vitro and in silico approaches.

Structure activity relationship of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives as P2Y6 receptor antagonists.

Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2H-chromene antagonist 3 of the Gq-coupled P2Y6 receptor (P2Y6R) were synthesized using a Sonogashira reaction to replace a 6-iodo group. The analogues were tested in a functional assay consisting of inhibition of calcium mobilization in P2Y6R-expressing astrocytoma cells elicited by native P2Y6R agonist UDP. 6-Ethynyl and 6-cyano groups were installed, and the alkynes were extended through both alkyl and aryl spacers. The most potent antagonists, with IC50 of ~1 µM, were found to be trialkylsilyl-ethynyl 7 and 8 (3-5 fold greater affinity than reference 3), t-butyl prop-2-yn-1-ylcarbamate 14 and p-carboxyphenyl-ethynyl 16 derivatives, and 3 and 8 displayed surmountable antagonism of UDP-induced production of inositol phosphates. Other chain-extended terminal carboxylate derivatives were less potent than the corresponding methyl ester derivatives. Thus, the 6 position in this chromene series is suitable for derivatization with flexibility of substitution, even with sterically extended chains, without losing P2Y6R affinity. However, a 3-carboxylic acid or 3-ester substitution did not serve as a nitro bioisostere, as the affinity was eliminated. These compounds provide additional ligand tools for the underexplored P2Y6R, which is a target for inflammatory, neurodegenerative and metabolic diseases.

Structure-Activity Relationship of Heterocyclic P2Y14 Receptor Antagonists: Removal of the Zwitterionic Character with Piperidine Bioisosteres.

A known zwitterionic, heterocyclic P2Y14R antagonist 3a was substituted with diverse groups on the central phenyl and terminal piperidine moieties, following a computational selection process. The most potent analogues contained an uncharged piperidine bioisostere, prescreened in silico, while an aza-scan (central phenyl ring) reduced P2Y14R affinity. Piperidine amide 11, 3-aminopropynyl 19, and 5-(hydroxymethyl)isoxazol-3-yl) 29 congeners in the triazole series maintained moderate receptor affinity. Adaption of 5-(hydroxymethyl)isoxazol-3-yl gave the most potent naphthalene-containing (32; MRS4654; IC50, 15 nM) and less active phenylamide-containing (33) scaffolds. Thus, a zwitterion was nonessential for receptor binding, and molecular docking and dynamics probed the hydroxymethylisoxazole interaction with extracellular loops. Also, amidomethyl ester prodrugs were explored to reversibly block the conserved carboxylate group to provide neutral analogues, which were cleavable by liver esterase, and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2Y14R antagonists for in vivo application.