Effect of anti-inflammatory treatments on patient outcomes and concentrations of inflammatory modulators in the post-surgical and post-traumatic tibiofemoral joint setting: a narrative review.

Background and Objective: There are several anti-inflammatory therapeutic options that can be used in the context of post-surgical and post-traumatic knee settings. Each of these options carries with it certain benefits, as well as potential issues depending on the duration and administration of each therapy. An understanding of how these anti-inflammatory drugs modulate various biomarkers of inflammation is also necessary in understanding how they can affect patient and objective outcomes following acute knee injury or surgery. This review covers the many traditional therapeutic options that have been used in treating knee injuries, as well as some natural therapeutics that have shown anti-inflammatory properties. Methods: A current review of the literature was conducted and synthesized into this narrative review. Key Content and Findings: Many traditional anti-inflammatory therapeutics have been shown to be beneficial in both post-traumatic and post-surgical tibiofemoral joint settings at reducing inflammation and improving patient outcomes. However, many of these treatments have risks associated with them, which becomes problematic with prolonged, repeated administration. Natural anti-inflammatory compounds may also have some benefit as adjunctive treatment options in these settings. Conclusions: There are multiple different therapeutic options that can be used in acute knee settings, but the specific mechanism of injury or surgical context should be weighed when determining the best clinical approach.

Guardians of the Genome: How the Single-Stranded DNA-Binding Proteins RPA and CST Facilitate Telomere Replication.

Telomeres act as the protective caps of eukaryotic linear chromosomes; thus, proper telomere maintenance is crucial for genome stability. Successful telomere replication is a cornerstone of telomere length regulation, but this process can be fraught due to the many intrinsic challenges telomeres pose to the replication machinery. In addition to the famous "end replication" problem due to the discontinuous nature of lagging strand synthesis, telomeres require various telomere-specific steps for maintaining the proper 3' overhang length. Bulk telomere replication also encounters its own difficulties as telomeres are prone to various forms of replication roadblocks. These roadblocks can result in an increase in replication stress that can cause replication forks to slow, stall, or become reversed. Ultimately, this leads to excess single-stranded DNA (ssDNA) that needs to be managed and protected for replication to continue and to prevent DNA damage and genome instability. RPA and CST are single-stranded DNA-binding protein complexes that play key roles in performing this task and help stabilize stalled forks for continued replication. The interplay between RPA and CST, their functions at telomeres during replication, and their specialized features for helping overcome replication stress at telomeres are the focus of this review.

Outcomes of Interfacility VV-Extracorporeal Membrane Oxygenation Transfers: A Multicenter Study.

As the availability of extracorporeal membrane oxygenation (ECMO) expands, so has the need for interfacility transfer to ECMO centers. However, the impact of these transfers is unknown. We hypothesized that interfacility transfers would be associated with increased complications and mortality. This retrospective cohort study includes adult patients treated with venovenous (VV) ECMO at all four adult ECMO centers comprising our statewide registry. Complications, mortality, ECMO duration, length of stay, and disposition were compared based on cannulation at an ECMO center versus outside hospital and transferred by air versus ground after adjusting for baseline covariates/parameters. The study included 420 adult patients, 36% of whom were cannulated at an outside institution before transfer. Of these, 63% were transported by ground and the remainder by air. Risk adjusted logistic regression revealed similar odds of mortality between those cannulated at ECMO centers versus referring hospital and then transported (odds ratio [OR] = 0.77, confidence interval [CI] = 0.49-1.22). This study supports the practice of interfacility ECMO transfer.

Inconsistent Return to Sport Despite Improved Outcomes After Re-revision Anterior Cruciate Ligament Reconstruction: An Updated Systematic Review.

PURPOSE: The primary objective was to systematically review the literature evaluating patient-reported outcomes and return to sport after re-revision anterior cruciate ligament reconstruction (ACLR) procedures. The secondary objectives were 2-fold: to identify the risk factors that lead to revision ACLR failure and to assess the secondary knee structure injuries after the initial revision ACLR. METHODS: A systematic review of the literature was performed using the MEDLINE/PubMed and Cochrane databases. The inclusion criteria were outcomes of re-revision ACLR, minimum of 2 years' follow-up, human studies, and English language. Basic science articles, epidemiologic studies, editorials, surgical technique articles, surveys, cadaveric studies, and animal studies were excluded. RESULTS: Fifteen studies met the inclusion criteria and were considered for review. There were 6 Level III and 9 Level IV studies that included 399 patients undergoing re-revision ACLR. The rate of concomitant meniscal lesions at the time of re-revision ranged from 35% to 90%. The prevalence of concomitant cartilaginous lesions at the time of re-revision ranged from 13.6% to 90%. Compared with preoperative scores, patient-reported outcomes overall improved after re-revision ACLR, with mean preoperative Lysholm scores ranging from 38.4 to 73.15 that improved to postoperative scores ranging from 68 to 87.8. However, return to sport at preinjury levels was inconsistent, with rates ranging from 12.5% to 80%. CONCLUSIONS: Re-revision ACLR was found to restore knee stability and improve functional outcomes. Despite this improvement, there was a low rate of return to sport at the preinjury level. Functional outcomes were also inferior when compared with primary ACLR. In addition, concomitant knee pathologies were found to rise in prevalence compared with revision and primary ACLR cases. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies.

Extracorporeal Membrane Oxygenation Patient Outcomes Following Restrictive Blood Transfusion Protocol.

OBJECTIVES: To investigate the effect of a restrictive blood product utilization protocol on blood product utilization and clinical outcomes. DESIGN: We retrospectively reviewed all adult extracorporeal membrane oxygenation (ECMO) patients from January 2019 to December 2021. The restrictive protocol, implemented in March 2020, was defined as transfusion of blood products for a hemoglobin level less than 7, platelet levels less than 50, and/or fibrinogen levels less than 100. Subgroup analysis was performed based on the mode of ECMO received: venoarterial ECMO, venovenous ECMO, and ECMO support following extracorporeal cardiopulmonary resuscitation (ECPR). SETTING: M Health Fairview University of Minnesota Medical Center. PATIENTS: The study included 507 patients. INTERVENTIONS: One hundred fifty-one patients (29.9%) were placed on venoarterial ECMO, 70 (13.8%) on venovenous ECMO, and 286 (56.4%) on ECPR. MEASUREMENTS AND MAIN RESULTS: For patients on venoarterial ECMO (48 [71.6%] vs. 52 [63.4%]; p = 0.374), venovenous ECMO (23 [63.9%] vs. 15 [45.5%]; p = 0.195), and ECPR (54 [50.0%] vs. 69 [39.2%]; p = 0.097), there were no significant differences in survival on ECMO. The last recorded mean hemoglobin value was also significantly decreased for venoarterial ECMO (8.10 [7.80-8.50] vs. 7.50 [7.15-8.25]; p = 0.001) and ECPR (8.20 [7.90-8.60] vs. 7.55 [7.10-8.88]; p < 0.001) following implementation of the restrictive transfusion protocol. CONCLUSIONS: These data suggest that a restrictive transfusion protocol is noninferior to ECMO patient survival. Additional, prospective randomized trials are required for further investigation of the safety of a restrictive transfusion protocol.

Reference standards for stress radiography measurements in knee ligament injury and instability: a systematic review.

PURPOSE: Stress radiographs are an easily accessible, cost-effective tool in the evaluation of acute and chronic ligament knee injuries. Stress radiographs provide an objective, quantifiable, and functional assessment of the injured ligament and can be a useful adjunct when planning surgical management and to objectively assess postoperative outcomes. This study aimed to review the literature reporting on stress radiographic techniques in evaluating knee ligament injury and instability and propose thresholds for interpreting stress radiography techniques. METHODS: The following three databases, OVID MEDLINE, the EMBASE library, and the Cochrane Controlled Trials Register, were systematically searched on January 23, 2023, for studies published from January 1970 to January 2023. The search extended to the reference lists of all relevant studies and orthopedic journals. Included studies were those that described a stress technique for the diagnosis of knee ligament injury; studies that reported a description or comparison of the accuracy and/or reliability of one or several stress radiography techniques, or studies that reported a comparison with alternative diagnostic modalities. RESULTS: Sixteen stress radiography techniques were reported for assessing the ACL with stress applied in the anterior plane, 10 techniques for assessing the PCL with stress applied in the posterior plane, 3 techniques for valgus stress, and 4 techniques for varus stress. The Telos device was the most commonly used stress device in the ACL and PCL studies. There was no consensus on the accuracy and reliability of stress radiography techniques for the diagnosis of any knee ligament injury. Stress radiography techniques were compared with alternative diagnostic techniques including instrumented arthrometry, MRI, and physical examination in 18 studies, with variability in the advantages and disadvantages of stress radiography techniques and alternatives. Analysis of results pooled from different studies demonstrated average delta gapping in knees with a completely injured ligament compared to the normal contralateral knee as per the following: for the ACL 4.9 ± 1.4 mm; PCL 8.1 ± 2.5 mm; MCL 2.3 ± 0.05 mm; and the FCL 3.4 ± 0.2 mm. CONCLUSION: Despite heterogeneity in the available literature with regard to stress examination techniques and device utilization, the data support that stress radiography techniques were accurate and reliable when compared to numerous alternatives in the diagnosis of acute and chronic knee ligament injuries. The present study also provides average increased ipsilateral compartment gapping/translation for specific knee ligament injuries based on the best available data. These values provide a reference standard for the interpretation of stress radiography techniques, help to guide surgical decision-making, and provide benchmark values for future investigations. LEVEL OF EVIDENCE: III.

RPA engages telomeric G-quadruplexes more effectively than CST.

G-quadruplexes (G4s) are a set of stable secondary structures that form within guanine-rich regions of single-stranded nucleic acids that pose challenges for DNA maintenance. The G-rich DNA sequence at telomeres has a propensity to form G4s of various topologies. The human protein complexes Replication Protein A (RPA) and CTC1-STN1-TEN1 (CST) are implicated in managing G4s at telomeres, leading to DNA unfolding and allowing telomere replication to proceed. Here, we use fluorescence anisotropy equilibrium binding measurements to determine the ability of these proteins to bind various telomeric G4s. We find that the ability of CST to specifically bind G-rich ssDNA is substantially inhibited by the presence of G4s. In contrast, RPA tightly binds telomeric G4s, showing negligible changes in affinity for G4 structure compared to linear ssDNAs. Using a mutagenesis strategy, we found that RPA DNA-binding domains work together for G4 binding, and simultaneous disruption of these domains reduces the affinity of RPA for G4 ssDNA. The relative inability of CST to disrupt G4s, combined with the greater cellular abundance of RPA, suggests that RPA could act as a primary protein complex responsible for resolving G4s at telomeres.

CST does not evict elongating telomerase but prevents initiation by ssDNA binding.

The CST complex (CTC1-STN1-TEN1) has been shown to inhibit telomerase extension of the G-strand of telomeres and facilitate the switch to C-strand synthesis by DNA polymerase alpha-primase (pol α-primase). Recently the structure of human CST was solved by cryo-EM, allowing the design of mutant proteins defective in telomeric ssDNA binding and prompting the reexamination of CST inhibition of telomerase. The previous proposal that human CST inhibits telomerase by sequestration of the DNA primer was tested with a series of DNA-binding mutants of CST and modeled by a competitive binding simulation. The DNA-binding mutants had substantially reduced ability to inhibit telomerase, as predicted from their reduced affinity for telomeric DNA. These results provide strong support for the previous primer sequestration model. We then tested whether addition of CST to an ongoing processive telomerase reaction would terminate DNA extension. Pulse-chase telomerase reactions with addition of either wild-type CST or DNA-binding mutants showed that CST has no detectable ability to terminate ongoing telomerase extension in vitro. The same lack of inhibition was observed with or without pol α-primase bound to CST. These results suggest how the switch from telomerase extension to C-strand synthesis may occur.