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.

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.

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.

Identification of B-cell-related HSPG2 and CDSN as susceptibility loci for Kawasaki disease.

Kawasaki disease (KD) is an acute pediatric vasculitis that predominantly affects children under the age of 5 years. To date, genome-wide association studies (GWAS) have identified several KD susceptibility genes (e.g., BLK, CD40, FCGR2A, BCL2L11, and IGHV), which are mainly involved in B cell immunity. In this study, we aimed to identify additional KD susceptibility genes mainly involved in B cell development and functions by analyzing our previous GWAS data and conducting a replication study using new sample. Initially, we selected 30 single nucleotide polymorphisms (SNPs) in B-cell-related genes that were significantly (P < 0.01) associated with KD in our previous GWAS analysis of 247 KD cases with complete type and 1,000 healthy controls. Replication study was performed by genotyping the new 837 KD case samples with Fluidigm system and comparing them with 3,553 control genotypes. Among the 30 candidate SNPs, two were significantly associated with KD (P < 0.001) in the replication study. An even greater association between these SNPs and KD was observed in the combined analysis of GWAS and replication samples: odds ratio (OR) = 1.97 (P = 8.61 × 10-6) for rs2270699 (nonsynonymous SNP: c.10588C > T, p.Arg3530Trp) in the heparan sulfate proteoglycan 2 (HSPG2) gene and OR = 1.28 (P = 1.34 × 10-6) for rs3130992 (intronic SNP) in both the corneodesmosin (CDSN) and psoriasis susceptibility 1 candidate 1 (PSORS1C1) genes. These results suggest that the B-cell-related genes, HSPG2 and CDSN or PSORS1C1, play a role in the development of 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.

Versatile Mesoporous Microblocks Prepared by Pattern-Induced Cracking of Colloidal Films.

Mesoporous microparticles have the potential to be used in various fields, such as energy generation, sensing, and the environmental field. Recently, the process of making homogeneous microparticles in an economical and environmentally friendly way has gained much attention. Herein, rectangular mesoporous microblocks of various designs are produced by manipulating the fragmentation of colloidal films consisting of micropyramids while controlling the notch angles of pyramidal edges. During calcination of the colloidal films, cracks are generated in the valleys of micropyramids acting as notches, and the angle of notches can be controlled by the prepattern underneath the micropyramids. By changing the location of notches with sharp angles, the shape of microblocks can be controlled with excellent uniformity. After detaching the microblocks from substrates, mesoporous microparticles of various sizes with multiple functions are easily produced. This study demonstrates anti-counterfeiting functions by encoding the rotation angles of rectangular microblocks of various sizes. In addition, the mesoporous microparticles can be utilized for separating desired chemicals mixed with chemicals of different charges. The method of fabricating size-tunable functionalized mesoporous microblocks can be a platform technology to prepare special films and catalysts and for environmental applications.

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.

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.

Ankle Pain After Medial Opening-Wedge High Tibial Osteotomy in Patients With Knee Osteoarthritis and Concurrent Ankle Osteoarthritis.

BACKGROUND: Medial opening-wedge high tibial osteotomy (MOWHTO) in patients with varus knee osteoarthritis (OA) causes changes to ankle and hindfoot alignment. However, the compensatory ability of the ankle and hindfoot varies according to the severity of ankle OA. PURPOSE: To investigate whether the changes in ankle symptoms and ankle and hindfoot alignments differ after MOWHTO according to the severity of preoperative ankle OA. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The data of 130 patients who were followed for ≥4 years were reviewed. Patients were classified into 2 groups according to their severity of ankle OA: group 1, modified Kellgren-Lawrence grade 0 and 1; group 2, grade ≥2. Four radiographic parameters were examined to evaluate ankle alignment: tibial plafond inclination, talar tilt, talar inclination, and tibial surface angle. The hindfoot alignment was evaluated using the varus-valgus angle (VVA) of the calcaneus. A visual analog scale (VAS) was used to evaluate ankle pain. The patient-reported outcome measure of the knee joint was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. RESULTS: There were 110 patients in group 1 and 20 patients in group 2. In group 2, the change in talar inclination after MOWHTO was significantly greater and the changes in tibial plafond inclination, talar tilt, and VVA were significantly smaller compared with in group 1 (all P < .05). Ankle pain VAS scores were more severe in group 2 than in group 1 pre- and postoperatively (all P < .05), and group 2 reported that ankle pain worsened postoperatively (P < .05). In both groups, knee WOMAC scores improved, and there were no differences between groups pre- or postoperatively (all P > .05). A multivariate regression analysis demonstrated that a small VVA change (odds ratio, 0.775; P = .027) and severe OA grade of the ankle joint preoperatively (Kellgren-Lawrence grades 2-4 vs 0 and 1; odds ratio, 4.241 [P = .046]) predicted increased ankle pain VAS scores after MOWHTO. CONCLUSION: Although the patient-reported outcome measures for the knee joint improved irrespective of the presence of ankle OA, ankle pain worsened after MOWHTO in patients with ankle OA. Inadequate compensatory change in hindfoot alignment increased ankle pain in these patients.

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.

Diagnosis of Central Sensitization and Its Effects on Postoperative Outcomes following Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

Central sensitization (CS) has been extensively researched as a cause of persistent pain after total knee arthroplasty (TKA). This systematic review study sought to investigate the diagnosis of CS in patients who underwent TKA for knee osteoarthritis (OA) and the effect of CS on clinical outcomes after TKA. Three comprehensive databases, including MEDLINE, EMBASE, and the Cochrane Library, were searched for studies that evaluated the outcomes of TKA in knee OA patients with CS. Data extraction, risk of bias assessment, and (where appropriate) meta-analysis were performed. The standardized mean difference (SMD) with a 95% confidence interval was used to assess the different scales of pain. A total of eight studies were selected, including two retrospective studies and five prospective observational studies. One study used additional randomized controlled trial data. Five studies were finally included in the meta-analysis. All studies had a minimum follow-up period of 3 months. The Central Sensitization Inventory (CSI), whole-body pain diagram, and quantitative sensory testing (QST) were used for measuring CS. The pooled analysis showed that patients with CS had more severe postoperative pain after TKA (SMD, 0.65; 95% CI, 0.40−0.90; p < 0.01) with moderate heterogeneity (I2 = 60%). In patients who underwent TKA with knee OA, CSI is most often used for the diagnosis of CS, and the QST and whole-body pain diagram are also used. CS is closely associated with more severe and persistent pain after TKA.

Patterning of interconnected human brain spheroids.

Brain spheroids are emerging as valuable in vitro models that are accelerating the pace of research in various diseases. For Alzheimer's disease (AD) research, these models are enhanced using genetically engineered human neural progenitor cells and novel cell culture methods. However, despite these advances, it remains challenging to study the progression of AD in vitro as well as the propagation of pathogenic amyloid-ß (Aß) and tau tangles between diseased and healthy neurons using the brain spheroids model. To address this need, we designed a microfluidic system of connected microwells for arranging two types of brain spheroids in complex patterns and enabling the formation of thick bundles of neurites between the brain spheroids and the accumulation of pathogenic Aß within the spheroids.

IgA Levels Are Associated with Coronary Artery Lesions in Kawasaki Disease.

BACKGROUND AND OBJECTIVES: Kawasaki disease (KD) is an acute systemic vasculitis that affects the coronary arteries. Abnormal immune reactions are thought to contribute to disease pathogenesis. The effect of immunoglobulin (Ig) isotype (IgG, IgA, IgM, and IgE) on inflammatory data and clinical outcomes of patients with KD was examined. METHODS: Ig levels in 241 patients with KD were measured during the acute, subacute, convalescent, and normal phases of the disease. RESULTS: Compared with reference Ig values, IgG, IgA, and IgM levels were significantly higher in the subacute phase, while IgE levels were elevated in 73.9% (178/241) of patients with KD in all clinical phases. However, high IgE levels were not associated with clinical outcomes, including intravenous immunoglobulin unresponsiveness and coronary artery lesions (CALs). Significantly more CALs were observed in the high IgA group than in the normal IgA group (44.7% vs. 20.8%, respectively; p<0.01). In addition, IgA levels in the acute phase (p=0.038) were 2.2-fold higher, and those in the subacute phase were 1.7-fold higher (p <0.001), in the CAL group than in the non-CAL group. IgA concentrations increased along with the size of the coronary artery aneurysm (p <0.001). Furthermore, there was a strong correlation between IgA levels and CAL size (r=0.435, p<0.001), with a high odds ratio of 2.58 (p=0.022). CONCLUSIONS: High IgA levels in patients with KD are prognostic for the risk of CALs.

Identification of rare coding variants associated with Kawasaki disease by whole exome sequencing.

Kawasaki disease (KD) is an acute pediatric vasculitis that affects genetically susceptible infants and children. To identify coding variants that influence susceptibility to KD, we conducted whole exome sequencing of 159 patients with KD and 902 controls, and performed a replication study in an independent 586 cases and 732 controls. We identified five rare coding variants in five genes (FCRLA, PTGER4, IL17F, CARD11, and SIGLEC10) associated with KD (odds ratio [OR], 1.18 to 4.41; p = 0.0027-0.031). We also performed association analysis in 26 KD patients with coronary artery aneurysms (CAAs; diameter > 5 mm) and 124 patients without CAAs (diameter < 3 mm), and identified another five rare coding variants in five genes (FGFR4, IL31RA, FNDC1, MMP8, and FOXN1), which may be associated with CAA (OR, 3.89 to 37.3; p = 0.0058-0.0261). These results provide insights into new candidate genes and genetic variants potentially involved in the development of KD and CAA.

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.

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 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.

A microscale, full-thickness, human skin on a chip assay simulating neutrophil responses to skin infection and antibiotic treatments.

Human skin models are essential for understanding dermatological diseases and testing new treatment strategies. The use of skin biopsies ex vivo is the most accurate model. However, their use is expensive and exposes the donor to pain and scarring. While bioengineered skin samples provide a cheaper alternative, they have limitations due to their simple structure and functionality compared to human skin. Here, we present a skin-on-a-chip device designed to study neutrophil responses to Staphylococcus aureus skin infections. We integrate human skin microcolumns, which have a cross-section that is ∼100 times smaller than traditional skin biopsies, are full-thickness, and are collected using minimally invasive skin sampling techniques. We use human neutrophils directly from one drop of blood, without the need for blood separation. Using the skin-on-a-chip device with skin and blood samples from healthy donors, we show that the neutrophil responses correlate with the bacteria-load in the skin. A pre-incubation step increases the number of migrating neutrophils in response to a low concentration of bacteria. Antibiotic treatment of S. aureus-infected skin samples reduces the number of neutrophils migrating towards the skin. Overall, we validate a skin on a chip model that enables the study of neutrophil migration to the skin in the presence of microbes and following the administration of antibiotics, two situations relevant to clinical cases of human skin and soft tissue infections.