Reprogramming the pancreatic cancer stroma and immune landscape by a silicasome nanocarrier delivering nintedanib, a protein tyrosine kinase inhibitor.

The prevailing desmoplastic stroma and immunosuppressive microenvironment within pancreatic ductal adenocarcinoma (PDAC) pose substantial challenges to therapeutic intervention. Despite the potential of protein tyrosine kinase (PTK) inhibitors in mitigating the desmoplastic stromal response and enhancing the immune milieu, their efficacy is curtailed by suboptimal pharmacokinetics (PK) and insufficient tumor penetration. To surmount these hurdles, we have pioneered a novel strategy, employing lipid bilayer-coated mesoporous silica nanoparticles (termed "silicasomes") as a carrier for the delivery of Nintedanib. Nintedanib, a triple PTK inhibitor that targets vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor receptors, was encapsulated in the pores of silicasomes via a remote loading mechanism for weak bases. This innovative approach not only enhanced pharmacokinetics and intratumor drug concentrations but also orchestrated a transformative shift in the desmoplastic and immune landscape in a robust orthotopic KRAS-mediated pancreatic carcinoma (KPC) model. Our results demonstrate attenuation of vascular density and collagen content through encapsulated Nintedanib treatment, concomitant with significant augmentation of the CD8+/FoxP3+ T-cell ratio. This remodeling was notably correlated with tumor regression in the KPC model. Strikingly, the synergy between encapsulated Nintedanib and anti-PD-1 immunotherapy further potentiated the antitumor effect. Both free and encapsulated Nintedanib induced a transcriptional upregulation of PD-L1 via the extracellular signal-regulated kinase (ERK) pathway. In summary, our pioneering approach involving the silicasome carrier not only improved antitumor angiogenesis but also profoundly reshaped the desmoplastic stromal and immune landscape within PDAC. These insights hold excellent promise for the development of innovative combinatorial strategies in PDAC therapy.

Life Expectancy of Patients Undergoing Total Knee Arthroplasty: Comparison With General Population.

BACKGROUND: This study aimed to analyze the life expectancy and cause of death in osteoarthritis (OA) patients who underwent total knee arthroplasty (TKA) and to identify risk factors that affect long-term mortality rate after TKA. METHODS: Among 601 patients, who underwent primary TKA due to OA by a single surgeon from July 2005 to December 2011, we identified patients who died after the operation using data obtained from the National Statistical Office of Korea. We calculated 5-, 10-, and 15-year survival rates of the patients and age-specific standardized mortality ratios (SMRs) compared to general population of South Korea according to the causes of death. We also identified risk factors for death. RESULTS: The 5-year, 10-year, and 15-year survival rates were 94%, 84%, and 75%, respectively. The overall age-specific SMR of the TKA cohort was lower than that of the general population (0.69; P < 0.001). Cause-specific SMRs for circulatory diseases, neoplasms, and digestive diseases after TKA were significantly lower than those of the general population (0.65, 0.58, and 0.16, respectively; all P < 0.05). Male gender, older age, lower body mass index (BMI), anemia, and higher Charlson comorbidity index (CCI) were significant factors associated with higher mortality after TKA. CONCLUSION: TKA is a worthwhile surgery that can improve life expectancy, especially from diseases of the circulatory system, neoplasms, and digestive system, in patients with OA compared to the general population. However, careful follow-up is needed for patients with male gender, older age, lower BMI, anemia, and higher CCI, as these factors may increase long-term mortality risk after TKA. LEVEL OF EVIDENCE: III.

Protein language models-assisted optimization of a uracil-N-glycosylase variant enables programmable T-to-G and T-to-C base editing.

Current base editors (BEs) use DNA deaminases, including cytidine deaminase in cytidine BE (CBE) or adenine deaminase in adenine BE (ABE), to facilitate transition nucleotide substitutions. Combining CBE or ABE with glycosylase enzymes can induce limited transversion mutations. Nonetheless, a critical demand remains for BEs capable of generating alternative mutation types, such as T>G corrections. In this study, we leveraged pre-trained protein language models to optimize a uracil-N-glycosylase (UNG) variant with altered specificity for thymines (eTDG). Notably, after two rounds of testing fewer than 50 top-ranking variants, more than 50% exhibited over 1.5-fold enhancement in enzymatic activities. When eTDG was fused with nCas9, it induced programmable T-to-S (G/C) substitutions and corrected db/db diabetic mutation in mice (up to 55%). Our findings not only establish orthogonal strategies for developing novel BEs but also demonstrate the capacities of protein language models for optimizing enzymes without extensive task-specific training data.

Predisposal of Interferon Regulatory Factor 1 Deficiency to Accumulate DNA Damage and Promote Osteoarthritis Development in Cartilage.

OBJECTIVE: Interferon regulatory factor 1 (IRF1) is a transcriptional regulator conventionally associated with immunomodulation. Recent molecular analyses mapping DNA binding sites of IRF1 have suggested its potential function in DNA repair. However, the physiologic significance of this noncanonical function remains unexplored. Here, we investigated the role of IRF1 in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation. METHODS: OA progression was examined in wild-type and Irf1-/- mice using histologic assessments and microcomputed tomography analysis of whole-joint OA manifestations and behavioral assessments of joint pain. An integrated analysis of assay for transposase-accessible chromatin with sequencing and whole transcriptome data was conducted for the functional assessment of IRF1 in chondrocytes. The role of IRF1 in DNA repair and senescence was investigated by assaying γ-H2AX foci and senescence-associated beta-galactosidase activity. RESULTS: Our genome-wide investigation of IRF1 footprinting in chondrocytes revealed its primary occupancies in the promoters of DNA repair genes without noticeable footprint patterns in those of interferon-responsive genes. Chondrocytes lacking IRF1 accumulated irreversible DNA damage under oxidative stress, facilitating their entry into cellular senescence. IRF1 was down-regulated in the cartilage of human and mouse OA. Although IRF1 overexpression did not elicit an inflammatory response in joints or affect OA development, genetic deletion of Irf1 caused enhanced chondrocyte senescence and exacerbated post-traumatic OA in mice. CONCLUSION: IRF1 offers DNA damage surveillance in chondrocytes, protecting them from oxidative stress associated with OA risk factors. Our study provides a crucial and cautionary perspective that compromising IRF1 activity renders chondrocytes vulnerable to cellular senescence and promotes OA development.

The Relationship between Western Ontario and McMaster Universities Osteoarthritis Index Score and Satisfaction after Total Knee Arthroplasty Changes Over Time.

This study aimed to determine whether there was a relationship between preoperative patient-reported outcome measures (PROMs) and satisfaction after total knee arthroplasty (TKA), and whether there was a relationship between the amount of improvement in PROM or final PROM and satisfaction and whether that relationship differed 1 and 2 years after TKA. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and satisfaction of 267 limbs who underwent TKA were analyzed. Logistic regression analysis was performed to determine whether there was a relationship between preoperative WOMAC or improvement in WOMAC or final WOMAC and satisfaction at 1 and 2 years after TKA. Pearson and Filon's z test was performed to determine whether there was a difference in evaluating satisfaction between the amount of improvement in WOMAC and final WOMAC. There was no significant relationship between preoperative WOMAC and satisfaction. A higher improvement in WOMAC total score and better final WOMAC total scores at 1 and 2 years after TKA were related to greater satisfaction. At 1 year after TKA, there was no significant difference in evaluating satisfaction between the amount of improvement in WOMAC and final WOMAC. However, 2 years after TKA, the final WOMAC function and total score were more related to satisfaction than the amount of improvement in WOMAC function and total score. In the early postoperative period, there was no difference in evaluating satisfaction between the amount of improvement in WOMAC and final WOMAC, whereas over time, the final WOMAC was more related to satisfaction.

Repair of medial meniscus posterior root tear is effective for root healing and cartilage regeneration in opening wedge high tibial osteotomy.

PURPOSE: This study aimed to determine whether the repair of a medial meniscus posterior root tear (MMPRT) is effective for MMPRT healing, cartilage regeneration, and clinical outcomes in opening wedge high tibial osteotomy (OWHTO). METHODS: This retrospective study included 80 patients who underwent OWHTO and subsequent second-look arthroscopy. The patients were divided into OWHTO-with-MMPRT-repair (n = 40) and OWHTO alone (n = 40) groups, and the healing rates (complete/partial/failure) were compared. Each group was further divided into over- and under-corrected subgroups to compare healing rates. The International Cartilage Repair Society (ICRS) grade, cartilage defect size, Koshino stage, ICRS cartilage repair assessment score of the medial femoral condyle (MFC), and International Knee Documentation Committee (IKDC) scores between the OWHTO-with-MMPRT-repair and OWHTO alone groups were compared according to whether microfracture was performed on the MFC. RESULTS: The overall healing rate of the MMPRT was higher in the OWHTO-with-MMPRT-repair group than that in the OWHTO alone group (P < 0.001). In addition, in the subgroup analysis, no difference in the MMPRT healing rate between the over-correction and under-correction groups when MMPRT repair was performed (n.s). In contrast, without MMPRT repair, the healing rate was lower in the under-correction group than that in the over-correction group (P = 0.03). Cartilage regeneration of the OWHTO-with-MMPRT-repair group was superior to that of the OWHTO alone group (P < 0.05). The IKDC subjective scores of the OWHTO-with-MMPRT-repair and OWHTO alone groups were 34.5 and 33.1 before surgery (n.s) and 50 and 47.2 at one year after surgery, respectively (n.s). These differences between the two groups for cartilage regeneration and IKDC subjective scores showed the same pattern regardless of microfractures. CONCLUSIONS: MMPRT repair during OWHTO might improve MMPRT healing, even with under-correction, and cartilage regeneration of MFC, regardless of microfracture. However, OWHTO with MMPRT repair might not improve short-term clinical outcomes compared to OWHTO alone. Further randomized clinical trials are necessary. LEVEL OF EVIDENCE: III, Retrospective cohort study.

Assessment of a novel deep learning-based software developed for automatic feature extraction and grading of radiographic knee osteoarthritis.

BACKGROUND: The Kellgren-Lawrence (KL) grading system is the most widely used method to classify the severity of osteoarthritis (OA) of the knee. However, due to ambiguity of terminology, the KL system showed inferior inter- and intra-observer reliability. For a more reliable evaluation, we recently developed novel deep learning (DL) software known as MediAI-OA to extract each radiographic feature of knee OA and to grade OA severity based on the KL system. METHODS: This research used data from the Osteoarthritis Initiative for training and validation of MediAI-OA. 44,193 radiographs and 810 radiographs were set as the training data and used as validation data, respectively. This AI model was developed to automatically quantify the degree of joint space narrowing (JSN) of medial and lateral tibiofemoral joint, to automatically detect osteophytes in four regions (medial distal femur, lateral distal femur, medial proximal tibia and lateral proximal tibia) of the knee joint, to classify the KL grade, and present the results of these three OA features together. The model was tested by using 400 test datasets, and the results were compared to the ground truth. The accuracy of the JSN quantification and osteophyte detection was evaluated. The KL grade classification performance was evaluated by precision, recall, F1 score, accuracy, and Cohen's kappa coefficient. In addition, we defined KL grade 2 or higher as clinically significant OA, and accuracy of OA diagnosis were obtained. RESULTS: The mean squared error of JSN rate quantification was 0.067 and average osteophyte detection accuracy of the MediAI-OA was 0.84. The accuracy of KL grading was 0.83, and the kappa coefficient between the AI model and ground truth was 0.768, which demonstrated substantial consistency. The OA diagnosis accuracy of this software was 0.92. CONCLUSIONS: The novel DL software known as MediAI-OA demonstrated satisfactory performance comparable to that of experienced orthopedic surgeons and radiologists for analyzing features of knee OA, KL grading and OA diagnosis. Therefore, reliable KL grading can be performed and the burden of the radiologist can be reduced by using MediAI-OA.

The transcription activity of OTX2 on p16 expression is significantly blocked by methylation of CpG shore in non-promoter of lung cancer cell lines.

Background: The aberrant expression of the classical tumor suppressor gene p16 is a frequent event in lung cancer mainly due to the hypermethylation of its 5'-cytosine-phosphate-guanine-3' island (Cgi). However, whether methylation happens in other regions and how p16 expression and function are affected are largely unknown. Methods: Clustered Regularly Interspaced Short Palindromic Repeats/dCas9 (CRISPR/dCas9) technology was used for methylation editing at specific site of p16. The effects of methylation editing were detected by 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, inner salt (MTS), transwell migration and wound healing tests. Chromatin immnoprecipitation-quantitative polymerase chain reaction (CHIP-qPCR) was performed to explore the impact of Cgi shore methylation on the binding abilities of transcription factors (TFs) including YY1, SP1, ZNF148 and OTX2 to p16 gene. A rescue experiment was performed to verify the regulatory effect of OTX2 on p16. The negative relationship between p16 expression and the methylation level of Cgi shore in non-promoter region was further verified with datasets from The Cancer Genome Atlas (TCGA) program and lung adenocarcinoma (LUAD) patients' samples. Results: The suppressive effect of p16 Cgi shore methylation on its expression was demonstrated in both HEK293 and A549 cells using CRISPR/dCas9-mediated specific site methylation editing. Methylation of the Cgi shore in the p16 non-promoter region significantly decreased its expression and promoted cell growth and migration. The ability of OTX2 bound to p16 was significantly reduced by 19.35% after methylation modification. Over-expression of OTX2 in A549 cells partly reversed the inhibitory effect of methylation on p16 expression by 19.04%. The verification results with TCGA and LUAD patients' samples supported that the p16 Cgi shore is a key methylation regulatory region. Conclusions: Our findings suggested that methylation of the Cgi shore in the p16 non-promoter region can hamper the transcriptional activity of OTX2, leading to a reduction in the expression of p16, which might contribute to the development of lung cancer.

Age and sex differences in coronal lower extremity alignment in a healthy Asian population.

BACKGROUND: The purpose of this study was to analyze the coronal alignment of lower extremities according to age and sex in a healthy population and demonstrate the differences. METHODS: Standing full-lower limb anteroposterior (AP) radiographs of healthy volunteers (670 males and 782 females) aged 18-69 years were retrospectively analyzed. The hip-knee-ankle angle (HKA), lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), joint line convergence angle and femoral bowing angle (FBA) were measured. The radiographic parameters were compared according to groups of age and sex. The proportion of volunteers with varus or valgus alignment more than 3° were also analyzed. RESULTS: With increasing age, HKA and LDFA varus increased. With increasing age, femoral medial bowing decreased. In addition, the HKA showed more varus alignment in males than in females (178.01° vs. 178.82°, P < 0.001). The MPTA was about 1° smaller in males than in females (P < 0.001). The proportion of patients with varus alignment of more than 3° increased with increasing age, with 16.9% in the 10-19 years old and 38.0% in the 60-69 years old groups. CONCLUSION: This study demonstrated that males showed more varus tibial alignments than females. Varus limb alignment, LDFA, and FBA also increases with age. In contrast, tibial alignment was constant across all age groups. Therefore, differences in lower extremity alignment according to age and sex should be considered in estimating individual prearthritic alignments.

Effects of Thrombin-Based Hemostatic Agent in Total Knee Arthroplasty: Meta-Analysis.

The effectiveness of Floseal, a thrombin-based hemostatic matrix, in total knee arthroplasty (TKA) in minimizing blood loss and transfusion requirements remains a topic of debate. This meta-analysis aims to evaluate the up-to-date randomized controlled trials (RCTs) on the efficacy and safety of Floseal in TKA. A comprehensive search was conducted in electronic databases to identify relevant RCTs. The methodological quality of the included studies was assessed, and data extraction was performed. The pooled effect sizes were calculated using standardized mean difference (SMD) or odds ratios (OR) with 95% confidence intervals (CIs). Eight studies involving 904 patients were included in the meta-analysis. The use of a thrombin-based hemostatic agent significantly reduced hemoglobin decline (SMD = -0.49, 95% CI: -0.92 to -0.07) and the risk of allogenic transfusion (OR = 0.45, 95% CI: 0.25 to 0.81) but showed no significant difference in the volume of drainage or total blood loss. Funnel plots showed no evidence of publication bias. This meta-analysis provides robust evidence supporting the effectiveness of Floseal in reducing hemoglobin decline and transfusion in TKA. Further well-designed RCTs with longer follow-up periods are warranted to assess long-term efficacy and safety.

The relationship between sovereign credit rating changes and firm risk.

Sovereign credit ratings, extensively studied for their influence on macroeconomics and country risk, have been less explored in the context of their impact on individual firms. This research delves into the effects of sovereign credit rating changes on firm risk. Our findings suggest that an upgrade in sovereign credit ratings decreases firm risk, while a downgrade amplifies it. Furthermore, the magnitude of a country's rating shift positively correlates with changes in firm risk. We also discern a contagion effect between trade-dependent countries: an elevated rating in one country diminishes the firm risk in its trading partner, and vice versa. When categorizing our data into developed and developing markets, we observe that firm risk in developed markets reacts more acutely to rating upgrades. Conversely, rating downgrades, whether domestic or in trade-associated countries, intensify firm risk in developing markets. A robustness check, which evaluates sovereign credit rating fluctuations outside of financial crises, corroborates our core findings.

A randomized controlled trial for comparing efficacy and safety between intraarticular polynucleotide and hyaluronic acid for knee osteoarthritis treatment.

Although the use of intra-articular polynucleotide (IA PN) injection as a viscosupplement for knee osteoarthritis (OA) treatment has been proposed, its efficacy and safety compared to high molecular weight hyaluronic acid (HMWHA) injection has not yet been established. The present double-blind, multicenter, randomized controlled trial aimed to investigate the efficacy and safety of IA PN injection compared to IA HMWHA injection. A total of 60 patients (15 men, 45 women, 64.5 ± 7.5 years) with knee OA (Kellgren-Lawrence grade 1-4) were randomly allocated to each group. All patients were given three IA injections of PN (n = 30) or HMWHA (n = 30) at intervals of 1 week. The primary endpoint was the change rate in weight-bearing pain (WBP) 16 weeks from the baseline. The secondary endpoint included multiple measurements: the change rate in WBP rate at 8 weeks; the change rate in pain level at rest and during walking at 8 and 16 weeks; the Korean-Western Ontario and McMaster University Osteoarthritis index; the Euro-Quality of Life-5 Dimension; Clinical Global Impression, Patient Global Impression at 8 and16 weeks, and total consumption of rescue medicine. The mean change rate in the WBP at 16 weeks from the baseline was - 54.0 ± 38.1% in the IA PN group and - 42.8 (± 35.8%) in the IA HMWHA group, and there was no significant difference between the two groups (p = 0.296). All secondary endpoints related with pain and functional outcome also showed no significant difference between the two groups. Pain at the injection site and swelling were reported as adverse events, and the incidence was similar between the two groups. IA PN showed comparable efficacy and safety to IA HMWHA at 3 times injection with an interval of 1 week. IA PN can be useful alternative to IA HMWHA for the treatment of knee OA.

Postoperative rehabilitation using a digital healthcare system in patients with total knee arthroplasty: a randomized controlled trial.

INTRODUCTION: Digital healthcare systems based on augmented reality (AR) show promise for postoperative rehabilitation. We compared the effectiveness of AR-based rehabilitation and conventional rehabilitation after total knee arthroplasty (TKA). MATERIALS AND METHODS: We randomly allocated 56 participants to digital healthcare rehabilitation group (DR group) and conventional rehabilitation group (CR group). Participants in the CR group performed brochure-based home exercises for 12 weeks, whereas those in the DR group performed AR-based home exercises that showed each motion on a monitor and provided real-time feedback. The primary outcome was change in 4-m gait speed. The secondary outcomes were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, health-related quality of life [assessed by the EuroQoL 5-Dimension 5-Level (EQ5D5L) questionnaire], pain [measured using a numeric rating scale (NRS)], Berg Balance Scale (BBS), range of motion (ROM), and muscle strength. Outcomes were measured at baseline (T0) and 3 (T1), 12 (T2), and 24 (T3) weeks after randomization. RESULTS: There was no significant difference in baseline characteristics of participants between two groups, except age and body mass index. No group difference was observed in 4-m gait speed (0.37 ± 0.19 and 0.42 ± 0.28 for the DR and CR groups, respectively; p = 0.438). The generalized estimating equation model revealed no significant group by time interaction regarding for 4-m gait speed, WOMAC, EQ5D5L, NRS, BBS, ROM, and muscle strength score. All outcomes were significantly improved in both groups (p < 0.001). CONCLUSION: The use of a digital healthcare system based on AR improved the functional outcomes, pain, and quality of life of patients after TKA. AR-based rehabilitation may be useful treatment as an alternative to conventional rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT04513353). Registered on August 9, 2020. http://clinicaltrials.gov/ct2/show/NCT04513353 .

Effect of Total Hip Arthroplasty on Ipsilateral Lower Limb Alignment and Knee Joint Space Width: Minimum 5-Year Follow-up.

BACKGROUND: This study aimed to 1) assess the effect of total hip arthroplasty (THA) on coronal limb alignment, namely, the hip-knee-ankle angle (HKA), 2) identify factors that determine changes in the HKA, and 3) determine whether alignment changes influence the knee joint space width. METHODS: We retrospectively evaluated 266 limbs of patients who underwent THA. Three types of prostheses with neck shaft angles (NSAs) of 132°, 135°, and 138° were used. Several radiographic parameters were measured in the preoperative and final radiographs (at least 5 years after THA). A paired t-test was used to confirm the effect of THA on HKA change. Multiple regression analysis was performed to identify radiographic parameters related to HKA changes following THA and changes in knee joint space width. Subgroup analyses were performed to reveal the effect of NSA change on the HKA change, and the proportion of total knee arthroplasty usage and changes in radiographic parameters between maintained joint space and narrowed joint space groups were compared. RESULTS: The preoperative mean HKA was 1.4° varus and increased to 2.7° varus after THA. This change was related to changes in the NSA, lateral distal femoral angle, and femoral bowing angle. In particular, in the group with a decrease in NSA of > 5°, the preoperative mean HKA was largely changed from 1.4° varus to 4.6° varus after THA. The prostheses with NSA of 132° and 135° also led to greater varus HKA changes than those with an NSA of 138°. Narrowing of the medial knee joint space was related to changes in the varus direction of the HKA, decrease in NSA, increase in femoral offset. CONCLUSION: A large reduction in NSA can lead to considerable varus limb alignment after THA, which can have adverse effects on the medial compartment of the ipsilateral knee.

Differences in Resumption of Orthopedic Surgery According to Characteristics of Surgery during COVID-19 Pandemic: National Registry Data.

Background: Healthcare services have been restricted after the coronavirus disease 2019 (COVID-19) outbreak. With the pandemic still ongoing, the patterns of orthopedic surgery might have changed. The purpose of this study was to determine whether the reduced volumes of orthopedic surgery were recovered over time. Among the trauma and elective surgery, which accounted for most orthopedic surgical procedures, we also sought to elucidate whether the changes in the volumes of orthopedic surgery differed according to the type of surgery. Methods: The volumes of orthopedic surgery were analyzed using the Health Insurance Review and Assessment Service of Korea databases. The surgical procedure codes were categorized depending on the characteristics of the procedures. The actual volumes of surgery were compared with the expected volumes to elucidate the effect of COVID-19 on surgical volumes. The expected volumes of surgery were estimated using Poisson regression models. Results: The reducing effect of COVID-19 on the volumes of orthopedic surgery weakened as COVID-19 continued. Although the total volumes of orthopedic surgery decreased by 8.5%-10.1% in the first wave, those recovered to a 2.2%-2.8% decrease from the expected volumes during the second and third waves. Among the trauma and elective surgery, open reduction and internal fixation and cruciate ligament reconstruction decreased as COVID-19 continued, while total knee arthroplasty recovered. However, the volumes of hemiarthroplasty of the hip did not decrease through the year. Conclusions: The number of orthopedic surgeries, which had decreased due to COVID-19, tended to recover over time, although the pandemic was still ongoing. However, the degree of resumption differed according to the characteristics of surgery. The findings of our study will be helpful to estimate the burden of orthopedic surgery in the era of persistent COVID-19.

The limited use of a tourniquet during total knee arthroplasty under a contemporary enhanced recovery protocol has no meaningful benefit: a prospective randomized controlled trial.

PURPOSE: This prospective randomized controlled trial aimed to determine whether the limited use of tourniquets during total knee arthroplasty (TKA) would be more beneficial under the contemporary enhanced recovery after surgery (ERAS) protocol than the conventional use of tourniquets. METHODS: One hundred patients with knee osteoarthritis who underwent primary TKA were randomly assigned to the limited tourniquet (LT, n = 51) and conventional tourniquet (CT, n = 49) groups. Operation time, serial hemoglobin drops, calculated blood loss, transfusion rate, D-dimer levels, and the presence of deep vein thrombosis (DVT) were assessed. In addition, visual analog scale (VAS) scores for pain around the knee and thigh were measured while resting during the day, at night, and during ambulation. Opioid consumption, range of motion, knee circumference, and postoperative complications were also analyzed. Isokinetic muscle strength, knee injury and osteoarthritis outcome scores, and Euro-QoL-5D scores were also assessed before and 3 months after TKA. For statistical analysis, Chi-square and Fisher's exact tests were performed to compare the differences in categorical variables. Continuous variables were compared using an independent t test or Mann‒Whitney U test. RESULTS: The average tourniquet time was 46.7 min in the CT group and 5.4 min in the LT group. Knee pain on the first night after surgery was significantly higher in the CT group (3.2 vs. 4.6, p = 0.033). However, daytime pain in the thigh at 2 weeks and in the knee at 3 months after TKA were higher in the LT group than in the CT group (p = 0.048 and p = 0.036, respectively). The D-dimer level 3 months after TKA was also higher in the LT group than in the CT group (p = 0.028), but there was no difference in DVT incidence between the two groups (n.s.). Additionally, there were no significant differences in the other variables between the groups. CONCLUSIONS: Although the limited use of tourniquets did not increase the operation time, blood loss, or transfusion rate, this study found that the limited use of tourniquets would not provide additional meaningful benefit in reducing pain and early functional restoration after TKA when applying the ERAS protocol. LEVEL OF EVIDENCE: I.

Comparison of failure rates and functional outcomes between hamstring autografts and hybrid grafts in anterior cruciate ligament reconstruction: A systematic review and meta-analysis.

BACKGROUND: The viability of augmenting small-diameter hamstring autografts with allografts remains unclear. Recent studies have reported different clinical results after allograft augmentation. Hence, we sought to determine whether hamstring autografts and hybrid grafts differed in terms of failure rates and functional outcomes after anterior cruciate ligament (ACL) reconstruction. We also evaluated whether the results of the comparisons differed based on allograft sterilization methods. PATIENTS AND METHODS: This systematic review and meta-analysis were performed by searching the PubMed, Cochrane Library, and EMBASE databases to identify prospective or retrospective studies (evidence levels 1, 2, or 3) that compared the failure rates and functional outcomes of ACL reconstruction using autografts and hybrid grafts. RESULTS: We identified 15 relevant studies, including 1,521 patients, with 798 and 723 treated using autografts and hybrid grafts, respectively. Fourteen studies were retrospective comparative studies, and one was a prospective randomized controlled trial. Of these, three studies used non-irradiated allografts. In the analysis of all participants, no significant differences in failure rates and subjective International Knee Documentation Committee (IKDC) scores were observed between the autograft and hybrid graft groups. Comparing the autograft and hybrid graft groups that used non-irradiated allografts, no differences in the failure rates and subjective IKDC scores were also noted. Meanwhile, in the groups that used irradiated allograft, the autograft group demonstrated higher Lysholm knee scores and reduced anterior laxity than the hybrid graft group. DISCUSSION: Overall, ACL reconstruction using hybrid grafts may not reduce failure rates compared to reconstructions using hamstring autografts, although hybrid grafts with irradiation may decrease functional outcomes. LEVEL OF EVIDENCE: III; systematic review of level II and III studies.

Medial Meniscus Posterior Root Repair Restores Contact Pressure and Contact Area to Its Native State Even After Opening-Wedge High Tibial Osteotomy: A Cadaveric Biomechanical Study.

PURPOSE: To elucidate the effect of medial meniscus posterior root (MMPR) repair during opening-wedge high tibial osteotomy (OWHTO) in terms of contact pressure (CP) and contact area (CA). METHODS: Nine fresh-frozen human cadaveric knee specimens were included. Each specimen was tested under 9 conditions comprising 3 different degrees of correction during OWHTO (neutral, 5° of valgus, and 10° of valgus) and 3 different types of MMPR conditions (intact, torn, and repaired). The prepared specimens were attached to a customized tibiofemoral jig in a fully extended state. The CP and CA generated by a tibiofemoral axial load of 650 N was recorded using the Tekscan sensor's pressure mapping software. Statistical analysis was performed using a repeated measures analysis of variance. RESULTS: The increased CP and decreased CA in torn MMPR was decreased and increased, respectively, to the intact MMPR after repairing, irrespective of whether OWHTO was performed. The mean CP at a correction angle of 5° of valgus was 0.4067 ± 0.0768 MPa for intact MMPR, which increased to 0.7340 ± 0.1593 MPa for the torn MMPR and decreased to 0.3614 ± 0.0639 MPa for the repaired MMPR. In addition, the proportion of decrease in CP and increase in CA after MMPR repair was constant, compared with the torn MMPR, irrespective of the degree of correction during OWHTO. CONCLUSIONS: MMPR repair decreases CP and increases CA, irrespective of whether OWHTO is performed. The biomechanical advantage of repairing torn MMPR is maintained, regardless of the degree of correction during OWHTO. CLINICAL RELEVANCE: Both OWHTO and MMPR repair are known to protect the medial compartment of the knee. However, there are concerns in performing 2 procedures simultaneously. Results of our study showed that concurrent repair of the MMPR during OWHTO is useful for protecting the medial compartment of the knee with respect to tibiofemoral contact biomechanics.

Presence of Night Pain, Neuropathic Pain, or Depressive Disorder Does Not Adversely Affect Outcomes After Total Knee Arthroplasty: A Prospective Cohort Study.

BACKGROUND: A considerable proportion of patients warranting total knee arthroplasty (TKA) have night pain, neuropathic pain, and/or depressive disorder, which may not be resolved by TKA. This prospective, longitudinal cohort study aimed to document the prevalence of night pain, neuropathic pain, and depressive disorder in patients with advanced knee osteoarthritis undergoing TKA and to determine whether the specific coexisting pain and/or disorder at the time of TKA adversely affected postoperative outcomes. METHODS: In this study, 148 patients undergoing TKA were longitudinally evaluated. The presence of night pain, neuropathic pain (determined using Douleur Neuropathique 4 [DN4]) and depressive disorder (determined using the Patient Health Questionnaire-9 [PHQ-9]) was determined before and 6 weeks, 3 months and 1 year after TKA. In addition, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and EuroQol-5 Dimension (EQ-5D) scores were assessed before and 1 year after TKA. Potential associations of night pain, neuropathic pain, and/or depressive disorder with pre- and postoperative WOMAC and EQ-5D scores were examined in subgroup analyses. RESULTS: Preoperatively, 72% (n = 106) of patients reported night pain, and the prevalences of neuropathic pain and depressive disorder were 15% and 17%, respectively. Preoperatively, compared with patients without night pain, those with night pain had significantly poorer preoperative WOMAC scores, but no significant difference was seen between groups 1 year after TKA. Preoperatively, the WOMAC, EQ-5D, and EQ-5D health scores of patients with neuropathic pain were not significantly different from those of patients without neuropathic pain, and there was no difference in clinical outcome scores 1 year after TKA between these groups. Preoperatively, the patients with depressive disorder showed significantly poorer preoperative WOMAC, EQ-5D, and EQ-5D health scores than those without depressive disorder, but no significant differences in scores were observed 1 year after TKA between these groups. CONCLUSION: This study revealed a considerable prevalence of night pain, neuropathic pain, and depressive disorder in patients undergoing TKA and that patients with these specific conditions reported poorer functional and quality of life scores preoperatively. However, such adverse effects disappeared after TKA. Our study findings suggest that TKA can provide satisfactory outcomes for patients with these specific conditions.