Analysis of retinal and choroidal microvascular changes using optical coherence tomography and optical coherence tomography angiography in patients with acute leukemia.

PURPOSE: Although leukemic retinopathy accounts for 80% of ocular complications in acute leukemia, its pathogenesis remains unclear. To evaluate changes in retinal and choroicapillaris and structural parameters in patients with acute leukemia, we analyzed the correlation between vascular perfusion metrics and laboratory parameters and assessed the changes after hematopoietic stem cell transplantation (HSCT). METHODS: Herein, 104 eyes of 52 patients aged 18 and above with acute leukemia were enrolled. 80 eyes of 40 healthy patients were recruited as control participants. All participants underwent optical coherence tomography (OCT) and OCT angiography (OCTA) at baseline. RESULTS: Patients with acute leukemia had a significantly thicker ganglion cell-inner plexiform layer (GCIPL) and lower circularity index than the control participants. Post-HSCT perfusion metrics did not differ significantly, but parafoveal thickness decreased significantly. During the active phase of acute leukemia, lower platelet levels were associated with significant GCIPL thickening and increased foveal avascular zone and perimeter. D-dimer levels positively correlated with GCIPL thickness. CONCLUSION: Patients with acute leukemia had subclinical retinal microvascular deficits on OCTA and GCIPL thickening on OCT, possibly associated with bone marrow function. GCIPL thickness may indicate acute ischemia in such patients. Further studies must elucidate their clinical and prognostic significance.

Factors related to central nervous system involvement of primary vitreoretinal lymphoma.

PURPOSE: This single center retrospective study aimed to investigate the factors associated with central nervous system (CNS) involvement of primary vitreoretinal lymphoma (PVRL). METHODS: Clinical features of patients with PVRL (Group 1), those diagnosed with vitreoretinal lymphoma (VRL) after primary CNS lymphoma diagnosis (Group 2), and those concurrently diagnosed with CNS lymphoma and VRL (Group 3), were compared. The main outcomes included sex, age, types of treatment, survival, visual acuity, diagnostic methods, VRL recurrence, ocular manifestations, and interleukin levels in the aqueous humor. RESULTS: Groups 1, 2, and 3 included 66 eyes in 38 patients, 29 eyes in 18 patients, and 14 eyes in 8 patients, respectively. Group 3 had shorter overall survival (OS) than Groups 1 and 2 (P = 0.042 and P = 0.009, respectively). The three groups did not differ in progression-free survival (P = 0.060). The 5-year survival rates of Groups 1, 2, and 3 were 56.5%, 44.0%, and 25.0%, respectively (P = 0.001). Patients with CNS involvement in Group 1 exhibited VRL recurrence (P < 0.001), high interleukin-10 (P = 0.024), and sub-retinal pigment epithelium (RPE) infiltration (P = 0.009). Patients experiencing VRL recurrence in Group 1 tended to show CNS involvement (P < 0.001). CONCLUSION: Patients concurrently diagnosed with CNS lymphoma and VRL had a shorter OS and a lower 5-year survival rate. In patients with PVRL, the recurrence of VRL, high interleukin-10, and sub-RPE infiltration were associated with CNS involvement.

Central Sensitization and Neuropathic Pain Cumulatively Affect Patients Reporting Inferior Outcomes Following Total Knee Arthroplasty.

UPDATE: This article was updated on November 17, 2023, because of previous errors, which were discovered after the preliminary version of the article was posted online. On page 102, the text that had read "In a post hoc analysis of the preoperative results, Group 1 showed significantly inferior WOMAC pain, function, and total scores compared with Group 4 (p < 0.05 for all). Groups 2 and 3 showed worse preoperative WOMAC pain, function, and total subscores compared with Group 4 (p < 0.05 for all). These results remained the same at 2 years after surgery." now reads "In a post hoc analysis of the preoperative results, Groups 1, 2, and 3 showed significantly inferior WOMAC pain, function, and total scores compared with Group 4 (p < 0.05 for all). At 2 years postoperatively, Group 1 showed inferior WOMAC pain, function, and total scores compared with the other groups (p < 0.05 for all). Also, Groups 2 and 3 had worse WOMAC pain, function and total scores compared with Group 4 (p < 0.05 for all)." Also, on page 106, the title of Table IV, which had previously read "Inter-Group Comparison of Preoperative Scores (Post Hoc Analysis)" now reads "Inter-Group Comparison of Postoperative Scores (Post Hoc Analysis)."

Available studies on the relationship between central sensitization and neuropathic pain, and on their association with patient-reported outcome measures (PROMs), following total knee arthroplasty (TKA) are insufficient. The purpose of the present study was to investigate this association. A total of 316 patients who underwent primary unilateral TKA for the treatment of end-stage osteoarthritis (OA) of the knee were enrolled. Central sensitization was defined as a score of ≥40 on the Central Sensitization Inventory. Neuropathic pain was defined as a score of ≥19 on the painDETECT Questionnaire (PDQ). PROMs were also evaluated on the basis of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score preoperatively and at 2 years postoperatively. The patients were divided into 4 groups: Group 1 had both central sensitization and neuropathic pain, Group 2 had central sensitization only, Group 3 had neuropathic pain only, and Group 4 had neither central sensitization nor neuropathic pain. Preoperative and postoperative PROMs were compared among the groups. All individuals who participated in the study were Asian, especially Korean. Fifty-five patients (17.4%) had both central sensitization and neuropathic pain, 68 (21.5%) had central sensitization only, 35 (11.1%) had neuropathic pain only, and 158 (50.0%) had neither condition. All WOMAC subscores showed significant differences among the 4 groups before and after surgery (p < 0.05 for all). In a post hoc analysis of the preoperative results, Groups 1, 2, and 3 showed significantly inferior WOMAC pain, function, and total scores compared with Group 4 (p < 0.05 for all). At 2 years postoperatively, Group 1 showed inferior WOMAC pain, function, and total scores compared with the other groups (p < 0.05 for all). Also, Groups 2 and 3 had worse WOMAC pain, function and total scores compared with Group 4 (p < 0.05 for all). Each condition, central sensitization and neuropathic pain, was associated with inferior PROMs following TKA. Furthermore, patients with both central sensitization and neuropathic pain showed worse PROMs compared with patients with either condition alone or without either condition. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Detection of Prosthetic Loosening in Hip and Knee Arthroplasty Using Machine Learning: A Systematic Review and Meta-Analysis.

Background: prosthetic loosening after hip and knee arthroplasty is one of the most common causes of joint arthroplasty failure and revision surgery. Diagnosis of prosthetic loosening is a difficult problem and, in many cases, loosening is not clearly diagnosed until accurately confirmed during surgery. The purpose of this study is to conduct a systematic review and meta-analysis to demonstrate the analysis and performance of machine learning in diagnosing prosthetic loosening after total hip arthroplasty (THA) and total knee arthroplasty (TKA). Materials and Methods: three comprehensive databases, including MEDLINE, EMBASE, and the Cochrane Library, were searched for studies that evaluated the detection accuracy of loosening around arthroplasty implants using machine learning. Data extraction, risk of bias assessment, and meta-analysis were performed. Results: five studies were included in the meta-analysis. All studies were retrospective studies. In total, data from 2013 patients with 3236 images were assessed; these data involved 2442 cases (75.5%) with THAs and 794 cases (24.5%) with TKAs. The most common and best-performing machine learning algorithm was DenseNet. In one study, a novel stacking approach using a random forest showed similar performance to DenseNet. The pooled sensitivity across studies was 0.92 (95% CI 0.84-0.97), the pooled specificity was 0.95 (95% CI 0.93-0.96), and the pooled diagnostic odds ratio was 194.09 (95% CI 61.60-611.57). The I2 statistics for sensitivity and specificity were 96% and 62%, respectively, showing that there was significant heterogeneity. The summary receiver operating characteristics curve indicated the sensitivity and specificity, as did the prediction regions, with an AUC of 0.9853. Conclusions: the performance of machine learning using plain radiography showed promising results with good accuracy, sensitivity, and specificity in the detection of loosening around THAs and TKAs. Machine learning can be incorporated into prosthetic loosening screening programs.

Does Generalized Joint Laxity Affect Postoperative Alignment and Clinical Outcomes Following Medial Opening-Wedge High Tibial Osteotomy?

BACKGROUND: The purpose of this study was to investigate whether generalized joint laxity affects the postoperative alignment and clinical outcomes of medial opening-wedge high tibial osteotomy (MOWHTO). METHODS: A total of 198 patients who underwent MOWHTO was divided into two groups according to absence or presence of generalized joint laxity. Generalized joint laxity was measured using the Beighton and Horan criteria, and a score of 4 or more out of 9 was defined as generalized joint laxity. A weight bearing line (WBL) ratio of 55% to 70% was considered an acceptable postoperative lower limb alignment range; WBL over 70% was defined as overcorrection and less than 55% as undercorrection. The WBL ratio was investigated before and 2 years after surgery, and the Western Ontario McMaster University Osteoarthritis Index scale score (WOMAC) was evaluated for patient-reported outcomes (PRO) of MOWHTO. There were 147 (73.7%) patients in the nongeneralized joint laxity group and 51 (26.3%) in the generalized joint laxity group. Preoperatively, there was no difference between the two groups in hip-knee-ankle (HKA) angle or WBL ratio (all P > .05). RESULTS: At 2 years postoperatively, the generalized joint laxity group showed significantly higher HKA angle and WBL ratio than the nongeneralized joint laxity group (all P < .05). There was a significant difference in the distribution ratio of undercorrection, normocorrection, and overcorrection patients between the two groups (P < .05). There were no differences between the two groups in preoperative and postoperative WOMAC scores (all, P > .05). CONCLUSION: The generalized joint laxity significantly affected postoperative over correction of alignment following MOWHTO. However, there was no significant difference in PRO between the patients who did and did not have generalized joint laxity after MOWHTO until 2 years.

Central Sensitization Is Associated with Inferior Patient-Reported Outcomes and Increased Osteotomy Site Pain in Patients Undergoing Medial Opening-Wedge High Tibial Osteotomy.

Background and Objectives: Studies have shown that centrally sensitized patients have worse clinical outcomes following total knee arthroplasty (TKA) than non-centrally sensitized patients. It is unclear whether central sensitization (CS) affects patient-reported outcomes (PROs) and/or level of osteotomy site pain in patients undergoing medial opening-wedge high tibial osteotomy (MOWHTO). The purpose of this study was to determine whether CS is associated with PROs and osteotomy site pain following MOWHTO. Materials and Methods: A retrospective evaluation was conducted on 140 patients with varus knee osteoarthritis (OA) who were treated with MOWHTO and monitored for two years. Before surgery, the Central Sensitization Inventory (CSI) was used to assess CS status, and a CSI of 40 or higher was considered indicative of CS. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and pain visual analogue scale (VAS) were used to assess PROs. The minimal clinically important difference (MCID) for the WOMAC was set as 4.2 for the pain subscore, 1.9 for the stiffness subscore, 10.1 for the function subscore, and 16.1 for the total based on the results of a previous study. The WOMAC score, pain VAS score of the osteotomy site, and the achievement rates of WOMAC MCID were compared between the CS and non-CS groups. Results: Thirty-seven patients were assigned to the CS group, whereas 84 were assigned to the non-CS group. Before surgery, the CS group showed a higher WOMAC score than the non-CS group (58.7 vs. 49.4, p < 0.05). While there was a statistically significant improvement in WOMAC subscores (pain, stiffness, function, and total) for both groups at two years after surgery (all p < 0.05), the CS group had a higher WOMAC score than the non-CS group (37.1 vs. 21.8, p < 0.05). The CS group showed significantly inferior results in pre- and postoperative changes of WOMAC subscores (pain, function, and total) relative to the non-CS group (all p < 0.05). In addition, pain at the osteotomy site was more severe in the CS group than in the non-CS group at two years after surgery (4.8 vs. 2.2, p < 0.05). Patients with CS had worse MCID achievement rates across the board for WOMAC pain, function, and total scores (all p < 0.05) compared to the non-CS group. Conclusions: Centrally sensitized patients following MOWHTO had worse PROs and more severe osteotomy site pain compared to non-centrally sensitized patients. Furthermore, the WOMAC MCID achievement rate of patients with CS was lower than that of patients without CS. Therefore, appropriate preoperative counseling and perioperative pain management are necessary for patients with CS undergoing MOWHTO. Level of Evidence: Level III, case-control study.

Identification of SAMD9L as a susceptibility locus for intravenous immunoglobulin resistance in Kawasaki disease by genome-wide association analysis.

Kawasaki disease (KD) is a systemic vasculitis affecting infants and children; it manifests as fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) treatment effectively attenuates the fever and systemic inflammation. However, 10-20% patients are unresponsive to IVIG. To identify genetic variants influencing IVIG non-response in KD, a genome-wide association study (GWAS) and a replication study were performed using a total of 148 IVIG non-responders and 845 IVIG-responders in a Korean population. rs28662 in the sterile alpha motif domain-containing protein 9-like (SAMD9L) locus showed the most significant result in the joint analysis of GWAS and replication samples (odds ratio (OR) = 3.47, P = 1.39 × 10-5). The same SNP in the SAMD9L locus was tested in the Japanese population, and it revealed a more significant association in a meta-analysis with Japanese data (OR = 4.30, P = 5.30 × 10-6). These results provide new insights into the mechanism of IVIG response in KD.

Quantitative and multiplex microRNA assays from unprocessed cells in isolated nanoliter well arrays.

MicroRNAs (miRNAs) have recently emerged as promising biomarkers for the profiling of diseases. Translation of miRNA biomarkers to clinical practice, however, remains a challenge due to the lack of analysis platforms for sensitive, quantitative, and multiplex miRNA assays that have simple and robust workflows suitable for translation. The platform we present here utilizes functionalized hydrogel posts contained within isolated nanoliter well reactors for quantitative and multiplex assays directly from unprocessed cell samples without the need of prior nucleic acid extraction. Simultaneous reactor isolation and delivery of miRNA extraction reagents is achieved by sealing an array of wells containing the functionalized hydrogel posts and cells against another array of wells containing lysis and extraction reagents. The nanoliter well array platform features >100× better sensitivity compared to previous technology utilizing hydrogel particles without relying on signal amplification and enables >100 parallel assays in a single device. These advances provided by this platform lay the groundwork for translatable and robust analysis technologies for miRNA expression profiling in samples with small populations of cells and in precious, material-limited samples.

Synthesis of Cell-Adhesive Anisotropic Multifunctional Particles by Stop Flow Lithography and Streptavidin-Biotin Interactions.

Cell-adhesive particles are of significant interest in biotechnology, the bioengineering of complex tissues, and biomedical research. Their applications range from platforms to increase the efficiency of anchorage-dependent cell culture to building blocks to loading cells in heterogeneous structures to clonal-population growth monitoring to cell sorting. Although useful, currently available cell-adhesive particles can accommodate only homogeneous cell culture. Here, we report the design of anisotropic hydrogel microparticles with tunable cell-adhesive regions as first step toward micropatterned cell cultures on particles. We employed stop flow lithography (SFL), the coupling reaction between amine and N-hydroxysuccinimide (NHS) and streptavidin-biotin chemistry to adjust the localization of conjugated collagen and poly-L-lysine on the surface of microscale particles. Using the new particles, we demonstrate the attachment and formation of tight junctions between brain endothelial cells. We also demonstrate the geometric patterning of breast cancer cells on particles with heterogeneous collagen coatings. This new approach avoids the exposure of cells to potentially toxic photoinitiators and ultraviolet light and decouples in time the microparticle synthesis and the cell culture steps to take advantage of the most recent advances in cell patterning available for traditional culture substrates.

Common variants in the CRP promoter are associated with a high C-reactive protein level in Kawasaki disease.

Kawasaki disease (KD) is an acute self-limiting form of vasculitis that afflicts infants and children and manifests as fever and signs of mucocutaneous inflammation. Children with KD show various laboratory inflammatory abnormalities, such as elevations in their white blood cell (WBC) count, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). We here performed a genome-wide association study (GWAS) of 178 KD patients to identify the genetic loci that influence 10 important KD laboratory markers: WBC count, neutrophil count, platelet count, CRP, ESR, hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and total protein. A total of 165 loci passed our arbitrary stage 1 threshold for replication (p < 1 × 10(-5)). Of these, only 2 SNPs (rs12068753 and rs4786091) demonstrated a significant association with the CRP level in replication study of 473 KD patients (p < 0.05). The SNP located at the CRP locus (rs12068753) demonstrated the most significant association with CRP in KD patients (beta = 4.73 and p = 1.20 × 10(-6) according to the stage 1 GWAS; beta = 3.65 and p = 1.35 × 10(-8) according to the replication study; beta = 3.97 and p = 1.11 × 10(-13) according to combined analysis) and explained 8.1% of the phenotypic variation observed. However, this SNP did not demonstrate any significant association with CRP in the general population (beta = 0.37 and p = 0.1732) and only explained 0.1% of the phenotypic variation in this instance. Furthermore, rs12068753 did not affect the development of coronary artery lesions or intravenous immunoglobulin resistance in KD patients. These results indicate that common variants in the CRP promoter can play an important role in the CRP levels in KD.

Approach for epiduroscopic laser neural decompression in case of the sacral canal stenosis.

Epiduroscopy is very useful in the treatment of not only low back pain caused by failed back surgery syndrome, epidural scar or herniated disc but also by chronic refractory low back pain which does not respond to interventional conservative treatment including fluoroscopically-directed epidural steroid injections and percutaneous adhesiolysis. Because cauterization using a laser fiber has become recently available, a wider opening is required to enter into the sacral canal in the case of epiduroscopic laser neural decompression (ELND). However, in a few patients, it is difficult to insert a device into the epidural space due to stenosis around the opening, and there is no alternative method. Herein, we report a case where a hiatus rasp specially designed for such patients was used to perform the operation.

Frequent amplification of CENPF, GMNN and CDK13 genes in hepatocellular carcinomas.

Genomic changes frequently occur in cancer cells during tumorigenesis from normal cells. Using the Illumina Human NS-12 single-nucleotide polymorphism (SNP) chip to screen for gene copy number changes in primary hepatocellular carcinomas (HCCs), we initially detected amplification of 35 genes from four genomic regions (1q21-41, 6p21.2-24.1, 7p13 and 8q13-23). By integrated screening of these genes for both DNA copy number and gene expression in HCC and colorectal cancer, we selected CENPF (centromere protein F/mitosin), GMNN (geminin, DNA replication inhibitor), CDK13 (cyclin-dependent kinase 13), and FAM82B (family with sequence similarity 82, member B) as common cancer genes. Each gene exhibited an amplification frequency of ~30% (range, 20-50%) in primary HCC (n = 57) and colorectal cancer (n = 12), as well as in a panel of human cancer cell lines (n = 70). Clonogenic and invasion assays of NIH3T3 cells transfected with each of the four amplified genes showed that CENPF, GMNN, and CDK13 were highly oncogenic whereas FAM82B was not. Interestingly, the oncogenic activity of these genes (excluding FAM82B) was highly correlated with gene-copy numbers in tumor samples (correlation coefficient, r>0.423), indicating that amplifications of CENPF, GMNN, and CDK13 genes are tightly linked and coincident in tumors. Furthermore, we confirmed that CDK13 gene copy number was significantly associated with clinical onset age in patients with HCC (P = 0.0037). Taken together, our results suggest that coincidently amplified CDK13, GMNN, and CENPF genes can play a role as common cancer-driver genes in human cancers.

TNFR1 promoter -329G/T polymorphism results in allele-specific repression of TNFR1 expression.

Tumor necrosis factor (TNF) and the TNF receptor (TNFR) superfamily play very important roles for cell death as well as normal immune regulation. Dysregulation of TNF-TNFR superfamily gene expression will influence many biological processes, and contributes to human diseases, including cancer. We investigated the genetic alterations of the TNF-TNFR superfamily genes in hepatocellular carcinoma (HCC). Several genetic alterations were detected in the 44 TNF-TNFR superfamily genes by sequencing hepatocellular carcinoma DNA samples. In particular, we found that the TNFR1 promoter -329G/T polymorphism was strongly associated with primary HCC (odds ratio [OR]=5.22, p=0.0007). We also observed frequent loss of heterozygosity at the polymorphic TNFR1 -329G/T site in the primary tumor tissues, indicating that the polymorphic TNFR1 -329G/T site is very susceptible to genetic alterations in HCC. Furthermore, in the polymorphic TNFR1 -329G/T site, the T allele resulted in the repression of TNFR1 expression. Therefore, our results suggest that TNFR1 -329G/T polymorphism may play an important role in the development of HCC.

Identification of regulatory polymorphisms in the TNF-TNF receptor superfamily.

The tumor necrosis factor and TNF receptor (TNF-TNFR) superfamily plays very important roles in the pathogenesis of many immune-mediated diseases. Regulation of TNF-TNFR superfamily gene expression influences many aspects of the pathology associated with these diseases. In order to investigate genetic variations in the regulatory regions of the TNF-TNFR superfamily genes, promoter regions were screened by sequencing DNA samples from 24 unrelated Korean individuals. We identified a total of 68 single-nucleotide polymorphisms (SNPs) in the regulatory regions of the known TNF-TNFR superfamily genes, including 50 SNPs in the promoter regions, 16 SNPs in the 5'-UTR regions, and two SNPs in the coding regions of these genes. Among the 68 SNPs identified in this study, 25 SNPs were novel SNPs. Interestingly, the sequence alteration created by 11 SNPs completely abolished putative transcription factor binding sites in these alleles. These results suggest that these SNP sites can regulate gene expression by controlling the binding of transcription factors. The identification of function-altering SNPs in the promoter regions of the TNF-TNFR superfamily will facilitate efforts to understand the association of TNF-TNFR superfamily genes with several immune-mediated human diseases.

Identification of single nucleotide polymorphisms in the tumor necrosis factor (TNF) and TNF receptor superfamily in the Korean population.

The tumor necrosis factor (TNF) and TNF receptor (TNF-TNFR) superfamily plays crucial roles in immune regulation and host immune responses. The superfamily has been also associated with many immune-mediated diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, and diabetes. In order to investigate genetic variants of the TNF-TNFR superfamily, a total of 63 known single nucleotide polymorphisms (SNPs) in the coding region (cSNPs) of the TNF-TNFR superfamily genes were selected from the public SNP database. Among 63 cSNPs tested in this study, only 24 SNPs (38%) were validated to be polymorphic in the Korean population by primer extension-based SNP genotyping. By means of the new enhanced single strand conformational polymorphism (SSCP) method, we also identified a total of 78 SNPs, including 48 known SNPs and 30 novel SNPs, in the 44 human TNF-TNFR superfamily genes. The newly discovered SNPs in the TNF-TNFR superfamily genes revealed that the Korean population had very different patterns of allele frequency compared with African or white populations, whereas Korean allele frequencies were highly similar to those of Asian (correlation coefficient r = 0.88, p < 0.046). A higher similarity of allele frequency was observed between Korean and Japanese populations (r = 0.90, p < 0.001). The validated SNPs in the TNF-TNFR superfamily would be valuable for association studies with several immune-mediated human diseases.