Impact of Alignment and Alignment Correction on Outcomes Following Robotic Medial Unicompartmental Knee Arthroplasty.

BACKGROUND: The purpose of this study was to retrospectively examine the relationship between preoperative and postoperative alignment in robotic unicompartmental knee arthroplasty (UKA) and postoperative patient-reported outcome measures. METHODS: A retrospective review of 374 patients who underwent robotic-assisted UKA was conducted. Patient demographics, history, and preoperative and postoperative Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) scores were obtained via chart review. Average follow-up period was 2.4 years (range: 0.4 to 4.5 years) to chart review and 9.5 months (range: 6 to 48 months) to latest KOOS-JR. Preoperative and postoperative robotically-measured knee alignment was obtained from operative reports. Incidence of conversion to total knee arthroplasty (TKA) was determined by review of a health information exchange tool. RESULTS: Multivariate regressions showed no statistically significant relationship between preoperative alignment, postoperative alignment, or degrees of alignment correction and change in KOOS-JR score or achievement of KOOS-JR minimal clinically important difference (MCID) (P > .05). Patients who had >8 degrees of postoperative varus alignment had on average a 20% lower achievement of KOOS-JR MCID compared to patients who had <8 degrees of postoperative varus alignment; however, this difference was not statistically significant (P > .05). There were 3 patients who required conversion to TKA in the follow-up period, with no significant relationship to alignment variables (P > .05). CONCLUSION: There was no significant difference in KOOS-JR change for those patients who had a larger or smaller degree of deformity correction, and correction did not predict MCID achievement.

The Potential Value of Performing Preoperative Urinalysis Prior to Total Knee Arthroplasty.

BACKGROUND: Although the practice of checking a urinalysis prior to elective total knee arthroplasty (TKA) is relatively common, very little has been reported on the association between a preoperative urinary tract infection (UTI) and adverse events in primary TKA. The goal of this study is to investigate the risk of postoperative complication following TKA as it relates to preoperative UTI. METHODS: Patients undergoing TKA were queried in the National Surgical Quality Improvement Program. Morbid events were classified as minor (transfusion, pneumonia, wound dehiscence, UTI, and renal insufficiency) and serious (wound infection, thromboembolic event, renal failure, myocardial infarction, prolonged ventilation, unplanned intubation, sepsis, and death). Risk factors for adverse events were analyzed in both univariate and multivariate fashion. RESULTS: A total of 203,851 patients undergoing TKA met inclusion criteria and 507 patients had a UTI present at time of surgery (UTI PATOS). A propensity matched analysis controlling for age, gender, body mass index, operative year, and American Society of Anesthesiologists score identified 507 patients without a UTI PATOS to serve as the control group. Following adjustment for baseline characteristics, operative year, and American Society of Anesthesiologists score, UTI PATOS was associated with increased risk for serious adverse events (odds ratio [OR] 2.746, 95% confidence interval [CI] 1.546-4.878, P = .0006), occurrence of any morbid event (OR 1.894, 95% CI 1.299-2.761, P = .0009), and reoperation (OR 4, 95% CI 2.592-6.169, P < .0001). CONCLUSION: This study suggests that a UTI present at time of TKA increases the risk of multiple postoperative complications and reoperation.

LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs.

The transporter protein Large-neutral Amino Acid Transporter 1 (LAT-1, SLC7A5) is responsible for transporting amino acids such as tyrosine and phenylalanine as well as thyroid hormones, and it has been exploited as a drug delivery mechanism. Recently its role in cancer has become increasingly appreciated, as it has been found to be up-regulated in many different tumor types, and its expression levels have been correlated with prognosis. Substitution at the meta position of aromatic amino acids has been reported to increase affinity for LAT-1; however, the SAR for this position has not previously been explored. Guided by newly refined computational models of the binding site, we hypothesized that groups capable of filling a hydrophobic pocket would increase binding to LAT-1, resulting in improved substrates relative to parent amino acid. Tyrosine and phenylalanine analogs substituted at the meta position with halogens, alkyl and aryl groups were synthesized and tested in cis-inhibition and trans-stimulation cell assays to determine activity. Contrary to our initial hypothesis we found that lipophilicity was correlated with diminished substrate activity and increased inhibition of the transporter. The synthesis and SAR of meta-substituted phenylalanine and tyrosine analogs is described.

LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates.

Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood-brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine's carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure-activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e., Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA's are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.

Cutibacterium acnes Infection as a Cause of Nonunion After Ulnar-Shortening Osteotomy.

Ulnar-shortening osteotomy is a reliable solution to treat ulnar impaction syndrome, but it has a significant rate of nonunion as a known complication. Generally nonunion after the procedure is attributed to noninfectious causes. When infections happen, they follow the microbiological trends of nonunions elsewhere in the body. We present a case of ulnar-shortening osteotomy using an oblique-cut osteotomy system that resulted in septic nonunion. At the time of revision surgery, Cutibacterium acnes and Staphylococcus hominis were isolated from the osteotomy site. The patient was successfully treated using intravenous antibiotics and the two-stage Masquelet technique and eventually went on to bony union. As C acnes is rarely encountered in this context, this report highlights the need to consider all possible pathogens in the workup of a potentially septic nonunion. Surgeons should consider bacteria such as C acnes that require prolonged incubation for isolation from cultures, which may not be part of many institutions' usual protocol. [Orthopedics. 2024;47(4):e211-e213.].

The Impact of Social Determinants of Health on Outcomes and Complications After Total Knee Arthroplasty: An Analysis of Neighborhood Deprivation Indices.

BACKGROUND: Social determinants of health (SDOH) are important factors in the delivery of orthopaedic care. The purpose of this study was to investigate the relationship between outcomes following total knee arthroplasty (TKA) and both the Social Vulnerability Index (SVI) and the Area Deprivation Index (ADI). METHODS: The Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) database was utilized to identify TKA cases for inclusion. Demographic characteristics and medical history were documented. The SVI, its subthemes, and the ADI were analyzed. Outcome data included length of stay, discharge disposition, postoperative change in the Knee Injury and Osteoarthritis Outcome Score, Joint Replacement (KOOS, JR), 90-day incidences of emergency department (ED) visits, readmission, death, deep venous thrombosis (DVT) and/or pulmonary embolism (PE), periprosthetic fracture, implant failure, periprosthetic joint infection (PJI), and all-cause reoperation. Database cross-referencing was completed to document aseptic and septic revisions beyond 90 days postoperatively. Bivariate quartile-stratified and multivariable analyses were used to associate deprivation metrics with outcomes. RESULTS: A total of 19,321 TKA cases met inclusion criteria. Baseline patient characteristics varied among the SVI and/or ADI quartiles, with patients of non-White race and with a greater number of comorbidities noted in higher deprivation quartiles. Higher SVI and/or ADI quartiles were correlated with an increased rate of discharge to a skilled nursing facility (p < 0.05). A higher SVI and/or ADI quartile was associated with increased incidences of ED visits and readmissions postoperatively (p < 0.05). DVT and/or PE and long-term aseptic revision were the complications most strongly associated with higher deprivation metrics. Upon multivariable analysis, greater length of stay and greater incidences of ED visits, readmissions, DVT and/or PE, and aseptic revision remained significantly associated with greater deprivation based on multiple metrics. CONCLUSIONS: Greater deprivation based on multiple SVI subthemes, the composite SVI, and the ADI was significantly associated with increased length of stay, non-home discharge ED visits, and readmissions. The SVI and the ADI may be important considerations in the perioperative assessment of patients who undergo TKA. LEVEL OF EVIDENCE: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Patients With and Without Double Crush Syndrome Achieve Similar Rates of Clinical Improvement Following Carpal Tunnel Release.

BACKGROUND: The purpose of this study is to compare outcomes of carpal tunnel release (CTR) in patients with and without double crush syndrome (DCS), defined as concurrent carpal tunnel syndrome (CTS) and cervical radiculopathy at C5-T1 on preoperative nerve conduction studies. METHODS: Patients with preoperative nerve conduction studies who underwent unilateral, isolated CTR were retrospectively identified. All patients completed preoperative and 3-month postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity (UE) and pain interference (PI), and Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaires, and responded to the anchor question: "Since your treatment, how would you rate your overall function?" (much worse, worse, slightly worse, no change, slightly improved, improved, much improved). Preoperative, postoperative, and changes in scores for UE, PI, and QuickDASH were compared, as were the anchor question responses and rates of achieving the minimal clinically important difference (MCID). RESULTS: Sixty-three patients with DCS and 115 patients with CTS only were included. At 3- to 4-month follow-up, absolute and change in UE, PI, and QuickDASH scores were not statistically different between patients with DCS and CTS. Rates of anchor question response and MCID achievement were comparable for patients with CTS only and DCS on each questionnaire. The MCID achievement ranged from 48.4% to 68.8% in the unmatched cohort and 48.4% to 60% in the matched group. CONCLUSIONS: At 3 to 4 months, patients with DCS experience similar patient-reported symptomatic and functional improvement, and achieve MCID of outcome measures at comparable rates to patients with CTS only. For patients with nerve compression at the carpal tunnel and cervical spine, CTR is a reasonable first step prior to proceeding with cervical spine decompression.

Clinical Y-view versus 3-dimensional assessments of intramuscular fat in patients with full-thickness rotator cuff tears.

RATIONALE AND OBJECTIVES: Recent evidence suggests an inhomogeneous distribution of intramuscular rotator cuff fat infiltration (FI) in a small sample of individuals with rotator cuff tears, yet clinically just a few slices at the scapular Y-view are used to evaluate FI in patients with rotator cuff tears. The purpose of this study was to determine if assessment of FI using the scapular Y-view is representative of the entire muscle in patients with full-thickness rotator cuff tears, and whether this varies by tear size. MATERIALS AND METHODS: Patients (N = 25) diagnosed with full-thickness rotator cuff tear and confirmed with magnetic resonance imaging (MRI) were included. Fat-water sequences were used to objectively quantify mean FI (%) in the entire 3D muscle and the mean from 3 slices at the Y-view. Mixed-model 2 × 2 ANOVAs were used to assess for differences between methods, and if results vary by tear-size. RESULTS: There were no statistically significant differences between mean amount of FI of the entire 3D muscle and mean Y-view in the supraspinatus or infraspinatus muscles (p > 0.05). Additionally, this did not differ across tear size groups (p > 0.05). CONCLUSION: Results of this study suggest FI assessed in the Y-view is not different (mean difference < 1.0%) from FI of the entire 3D muscle in patients with full-thickness rotator cuff tears. Therefore, the clinical utility of evaluating rotator cuff intramuscular fat infiltration with the Y-view is further supported in patients with full-thickness rotator cuff tears across tear sizes.

Changing the Apoptosis Pathway through Evolutionary Protein Design.

One obstacle in de novo protein design is the vast sequence space that needs to be searched through to obtain functional proteins. We developed a new method using structural profiles created from evolutionarily related proteins to constrain the simulation search process, with functions specified by atomic-level ligand-protein binding interactions. The approach was applied to redesigning the BIR3 domain of the X-linked inhibitor of apoptosis protein (XIAP), whose primary function is to suppress the cell death by inhibiting caspase-9 activity; however, the function of the wild-type XIAP can be eliminated by the binding of Smac peptides. Isothermal calorimetry and luminescence assay reveal that the designed XIAP domains can bind strongly with the Smac peptides but do not significantly inhibit the caspase-9 proteolytic activity in vitro compared with the wild-type XIAP protein. Detailed mutation assay experiments suggest that the binding specificity in the designs is essentially determined by the interplay of structural profile and physical interactions, which demonstrates the potential to modify apoptosis pathways through computational design.

Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1).

The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.