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.

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.

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.

Risk Factors and Preventive Strategies for Perioperative Distal Femoral Fracture in Patients Undergoing Total Knee Arthroplasty.

Background and Objectives Perioperative distal femoral fracture is rare in patients undergoing total knee arthroplasty (TKA). In such rare cases, additional fixation might be required, and recovery can be delayed. Several studies have focused on perioperative distal femoral fractures in TKA, but there remains a lack of information on risk factors. The purpose of this study was to investigate risk factors for perioperative distal femoral fractures in patients undergoing TKA and suggest preventive strategies. Materials and Methods: This retrospective study included a total of 5364 TKA cases in a single institution from 2011 to 2022. Twenty-four distal femoral fractures occurred during TKA or within one month postoperatively (0.45%). Patient demographics, intraoperative findings, and postoperative progress were obtained from patient medical records and radiographs. Risk factors for fractures were analyzed using multivariate Firth logistic regression analysis. Results: Although all 24 distal femoral fractures occurred in female patients (24 of 4819 patients, 0.50%), the incidence rate of fracture between male and female patients was not significantly different (p = 0.165). The presence of osteoporosis and insertion of a polyethylene (PE) insert with knee dislocation were statistically significant risk factors (p = 0.009 and p = 0.046, respectively). However, multivariate logistic regression analysis showed that only osteoporosis with bone mineral density (BMD) < -2.8 (odds ratio (2.30), 95% CI (1.03-5.54), p = 0.043) was an independent risk factor for perioperative distal femoral fracture in TKA patients. Conclusions: Our results suggest that osteoporosis with BMD < -2.8 is a risk factor for distal femoral fractures in patients undergoing TKA. In these patients, careful bone cutting, adequate gap balancing, and especially the use of the sliding method for insertion of a PE insert are recommended as preventive strategies.

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.

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.

Association of an IGHV3-66 gene variant with Kawasaki disease.

In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10-9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10-10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

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.

Association of the IL16 Asn1147Lys polymorphism with intravenous immunoglobulin resistance in Kawasaki disease.

Kawasaki disease (KD) is an acute, self-limited vasculitis, mainly affecting children younger than 5 years old, with accompanying fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) is the standard treatment for KD; however, ~15% of patients are resistant to IVIG treatment. To identify protein coding genetic variants influencing IVIG resistance, we re-analyzed our previous genome-wide association study (GWAS) data from 296 patients with KD, including 101 IVIG non-responders and 195 IVIG responders. Five nonsynonymous SNPs (nsSNPs) in five immune-related genes, including a previously reported SAMD9L nsSNP (rs10488532; p.Val266Ile), were associated with IVIG non-response (odds ratio [OR] = 1.89-3.46, P = 0.0109-0.0035). In a replication study of the four newly-identified nsSNPs, only one in the interleukin 16 (IL16) gene (rs11556218, p.Asn1147Lys) showed a trend of association with IVIG non-response (OR = 1.54, P = 0.0078). The same IL16 nsSNP was more significantly associated with IVIG non-response in combined analysis of all data (OR = 1.64, P = 1.25 × 10-4). Furthermore, risk allele combination of the IL16 CT and SAMD9L TT nsSNP genotypes exhibited a very strong effect size (OR = 9.19, P = 3.63 × 10-4). These results implicate IL16 as involved in the mechanism of IVIG resistance in KD.

Identification of the TIFAB Gene as a Susceptibility Locus for Coronary Artery Aneurysm in Patients with Kawasaki Disease.

Kawasaki disease (KD) is a self-limiting systemic vasculitis of unknown etiology. KD is often complicated by coronary artery aneurysms (CAAs), which develop in about 20-25% of untreated children and 3-5% of children treated with intravenous immunoglobulin therapy. To identify the risk loci for CAA susceptibility in patients with KD, we performed a genome-wide association study (GWAS) using our previous Illumina HumanOmni1-Quad BeadChip data (296 KD patients) and a new replication study in an independent sample set (713 KD patients) by grouping KD patients without CAA (control) versus KD patients with extremely large aneurysms (diameter ≥ 5 mm) (case). Among 44 candidate single -nucleotide polymorphisms (SNPs) selected from the initial GWAS data (33 cases vs. 215 controls), a SNP (rs899162) located 7 kb upstream of the TIFAB gene on chromosome five was replicated in an independent sample (12 cases vs. 532 controls). In the combined analysis (45 cases vs. 747 controls), the SNP (rs899162) showed a highly significant association with CAA formation (diameter ≥ 5 mm) in patients with KD (odds ratio = 3.20, 95% confidence interval = 2.02-5.05, Pcombined = 1.95 × 10-7). These results indicate that the TIFAB gene may act as a CAA susceptibility locus in patients with KD.

Porous microwells for geometry-selective, large-scale microparticle arrays.

Large-scale microparticle arrays (LSMAs) are key for material science and bioengineering applications. However, previous approaches suffer from trade-offs between scalability, precision, specificity and versatility. Here, we present a porous microwell-based approach to create large-scale microparticle arrays with complex motifs. Microparticles are guided to and pushed into microwells by fluid flow through small open pores at the bottom of the porous well arrays. A scaling theory allows for the rational design of LSMAs to sort and array particles on the basis of their size, shape, or modulus. Sequential particle assembly allows for proximal and nested particle arrangements, as well as particle recollection and pattern transfer. We demonstrate the capabilities of the approach by means of three applications: high-throughput single-cell arrays; microenvironment fabrication for neutrophil chemotaxis; and complex, covert tags by the transfer of an upconversion nanocrystal-laden LSMA.

A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease.

Kawasaki disease (KD), a systemic vasculitis of infants and children, manifests as fever and mucocutaneous inflammation. Although its etiology is largely unknown, the epidemiological data suggest that genetic factors are important in KD susceptibility. To identify genetic variants influencing KD susceptibility, we performed a genome-wide association study (GWAS) and replication study using a total of 915 children with KD and 4553 controls in the Korean population. Six single-nucleotide polymorphisms (SNPs) in three loci were associated significantly with KD susceptibility (P<1.0 × 10-5), including the previously reported BLK locus (rs6993775, odds ratio (OR)=1.52, P=2.52 × 10-11). The other two loci were newly identified: NMNAT2 on chromosome 1q25.3 (rs2078087, OR=1.33, P=1.15 × 10-6) and the human leukocyte antigen (HLA) region on chromosome 6p21.3 (HLA-C, HLA-B, MICA and HCP5) (rs9380242, rs9378199, rs9266669 and rs6938467; OR=1.33-1.51, P=8.93 × 10-6 to 5.24 × 10-8). Additionally, SNP rs17280682 in NLRP14 was associated significantly with KD with a family history (18 cases vs 4553 controls, OR=6.76, P=5.46 × 10-6). These results provide new insights into the pathogenesis and pathophysiology of KD.

Governing Principles of Alginate Microparticle Synthesis with Centrifugal Forces.

A controlled synthesis of polymeric particles is becoming increasingly important because of emerging applications ranging from medical diagnostics to self-assembly. Centrifugal synthesis of hydrogel microparticles is a promising method, combining rapid particle synthesis and the ease of manufacturing with readily available laboratory equipment. This method utilizes centrifugal forces to extrude an aqueous polymer solution, sodium alginate (NaALG) through a nozzle. The extruded solution forms droplets that quickly cross-link upon contact with aqueous calcium chloride (CaCl2) solution to form hydrogel particles. The size distribution of hydrogel particles is dictated by the pinch-off behavior of the extruded solution through a balance of inertial, viscous, and surface tension stresses. We identify the parameters dictating the particle size and provide a numerical correlation predicting the average particle size. Furthermore, we create a phase map identifying different pinch-off regimes (dripping without satellites, dripping with satellites, and jetting), explaining the corresponding particle size distributions, and present scaling arguments predicting the transition between regimes. By shedding light on the underlying physics, this study enables the rational design and operation of particle synthesis by centrifugal forces.

Universal process-inert encoding architecture for polymer microparticles.

Polymer microparticles with unique, decodable identities are versatile information carriers with a small footprint. Widespread incorporation into industrial processes, however, is limited by a trade-off between encoding density, scalability and decoding robustness in diverse physicochemical environments. Here, we report an encoding strategy that combines spatial patterning with rare-earth upconversion nanocrystals, single-wavelength near-infrared excitation and portable CCD (charge-coupled device)-based decoding to distinguish particles synthesized by means of flow lithography. This architecture exhibits large, exponentially scalable encoding capacities (>10(6) particles), an ultralow decoding false-alarm rate (<10(-9)), the ability to manipulate particles by applying magnetic fields, and pronounced insensitivity to both particle chemistry and harsh processing conditions. We demonstrate quantitative agreement between observed and predicted decoding for a range of practical applications with orthogonal requirements, including covert multiparticle barcoding of pharmaceutical packaging (refractive-index matching), multiplexed microRNA detection (biocompatibility) and embedded labelling of high-temperature-cast objects (temperature resistance).

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.

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.

Sex-Specific Susceptibility Loci Associated With Coronary Artery Aneurysms in Patients With Kawasaki Disease.

BACKGROUND AND OBJECTIVES: Kawasaki disease (KD) is an acute vasculitis that primarily affects children under age 5 years. Approximately 20-25% of untreated children with KD and 3-5% of those treated with intravenous immunoglobulin therapy develop coronary artery aneurysms (CAAs). The prevalence of CAAs is much higher in male than in female patients with KD, but the underlying factors contributing to susceptibility to CAAs in patients with KD remain unclear. This study aimed to identify sex-specific susceptibility loci associated with CAAs in KD patients. METHODS: A sex-stratified genome-wide association study (GWAS) was performed using previously obtained GWAS data from 296 KD patients and a new replication study in an independent set of 976 KD patients by comparing KD patients without CAA (controls) and KD patients with aneurysms (internal diameter ≥5 mm) (cases). RESULTS: Six male-specific susceptibility loci, PDE1C, NOS3, DLG2, CPNE8, FUNDC1, and GABRQ (odds ratios [ORs], 2.25-9.98; p=0.00204-1.96×10-6), and 2 female-specific susceptibility loci, SMAD3 (OR, 4.59; p=0.00016) and IL1RAPL1 (OR, 4.35; p=0.00026), were significantly associated with CAAs in patients with KD. In addition, the numbers of CAA risk alleles additively contributed to the development of CAAs in patients with KD. CONCLUSIONS: A sex-stratified GWAS identified 6 male-specific (PDE1C, NOS3, DLG2, CPNE8, FUNDC1, and GABRQ) and 2 female-specific (SMAD3 and IL1RAPL1) CAA susceptibility loci in patients with KD.

Identification of KCNN2 as a susceptibility locus for coronary artery aneurysms in Kawasaki disease using genome-wide association analysis.

Kawasaki disease (KD) is often complicated by coronary artery lesions (CALs), including aneurysms. Because of the complications associated with KD, this disorder is the leading cause of acquired heart disease in children from developed countries. To identify genetic loci that confer a higher risk of developing CALs, we performed a case-control association study using previous genome-wide association study data for samples from KD cases only (n=186) by grouping KD patients without CALs (control: n=123) vs KD patients with extremely large aneurysms (diameter>5 mm) (case: n=17). Twelve loci with one or more sequence variants were found to be significantly associated with CALs (P<1 × 10(-5)). Of these, an SNP (rs17136627) in the potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2 (KCNN2) at 5q22.3 was validated in 32 KD patients with large aneurysms (diameter>5 mm) and 191 KD patients without CALs (odds ratio (OR)=12.6, P(combined)=1.96 × 10(-8)). This result indicates that the KCNN2 gene can have an important role in the development of coronary artery aneurysms in KD.

Recent advances in in vitro skin-on-a-chip models for drug testing.

INTRODUCTION: The skin is an organ that has the largest surface area and provides a barrier against external environment. While providing protection, it also interacts with other organs in the body and has implications for various diseases. Development of physiologically realistic in vitro models of the skin in the context of the whole body is important for studying these diseases and will be a valuable tool for pharmaceutical, cosmetics, and food industry. AREA COVERED: This article provides an overview of the skin structure, physiology, as well as drug metabolism in the skin, and dermatological diseases. We summarize various in vitro skin models currently available, as well as novel in vitro models based on organ-on-a-chip technology. We also explain the concept of multi-organ-on-a-chip and describe recent developments in this field aimed at recapitulating the interaction of the skin with other organs in the body. EXPERT OPINION: Recent developments in the organ-on-a-chip field have enabled the development of in vitro model systems that resemble human skin more closely than conventional models. In the near future, we will be seeing various model systems that allow researchers to study complex diseases in a more mechanistic manner, which will help the development of new pharmaceuticals for such diseases.