Comparison of safety and effectiveness between etanercept biosimilar LBEC0101 and reference in patients with rheumatoid arthritis in real-world data using the KURAMA cohort.

OBJECTIVES: Biosimilars are anticipated to be widely used in the treatment of rheumatoid arthritis (RA), owing to their cost efficiency; LBEC0101 was the first etanercept (ETN) biosimilar approved in Japan. However, there are limited real-world data comparing its safety and effectiveness with those of a reference product. METHODS: This study used data from the Kyoto University Rheumatoid Arthritis Management Alliance cohort, including patients with RA who received ETN therapy-ETN reference product (ETN-RP) or LBEC0101-between 2015 and 2021. Serum ETN levels were measured using liquid chromatography-tandem mass spectrometry. RESULTS: The 1-year continuation rates of ETN-RP and LBEC0101 were 58.7% and 74.4%, respectively. Effectiveness of treatment was evaluated in 18 patients; both products significantly reduced the 28-joint RA disease activity score and erythrocyte sedimentation rate (DAS28-ESR). Moreover, to determine equivalence, we analysed 11 patients who switched from ETN-RP to LBEC0101; the DAS28-ESR and serum ETN levels before and after switching were not significantly different. CONCLUSIONS: This real-world cohort study confirmed that the biosimilar of ETN, LBEC0101, was comparable to the reference product in terms of continuation rate, effectiveness at initiation of introduction, and effect persistence before and after switching in clinical practice.

Real-world comparative study of the efficacy of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

OBJECTIVE: This multicentre, retrospective study compared the efficacy and safety of tofacitinib, baricitinib, peficitinib and upadacitinib in real-world clinical settings after minimizing selection bias and adjusting the confounding patient characteristics. METHOD: The 622 patients were selected from the ANSWER cohort database and treated with tofacitinib (TOF), baricitinib (BAR), peficitinib (PEF) or upadacitinib (UPA). The patient's background was matched using propensity score-based inverse probability of treatment weighting (IPTW) among four treatment groups. The values of Clinical Disease Activity Index (CDAI), C-reactive protein (CRP), and modified Health Assessment Questionnaire (mHAQ) after drug initiation and the remission or low disease activity (LDA) rates of CDAI at 6 months after drug initiation were compared among the four groups. Further, the predictive factor for TOF and BAR efficacy was analysed. RESULTS: The retention and discontinuation rates until 6 months after drug initiations were not significantly different among the four JAK inhibitors treatment groups. Mean CDAI value, CDAI remission rate, and CDAI-LDA rate at 6 months after drug initiation were not significantly different among treatment groups. Baseline CDAI (TOFA: OR 1.09, P < 0.001; BARI: OR 1.07, P < 0.001), baseline CRP (TOFA: OR 1.32, P = 0.049), baseline glucocorticoid dose (BARI: OR 1.18, 95% CI 1.01-1.38, P = 0.035), a number of previous biological or targeted synthetic disease-modifying antirheumatic drugs (biological/targeted synthetic DMARDs) (BARI: OR 1.36, P = 0.004) were predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. CONCLUSION: The efficacy and safety of TOF, BAR, PEF and UPA were not significantly different for the treatment of patients with rheumatoid arthritis.

Genetic and histopathological analysis of spermatogenesis after short-term testicular torsion in rats.

BACKGROUND: Patients with testicular torsion (TT) may exhibit impaired spermatogenesis from reperfusion injury after detorsion surgery. Alteration in the expressions of spermatogenesis-related genes induced by TT have not been fully elucidated. METHODS: Eight-week-old Sprague-Dawley rats were grouped as follows: group 1 (sham-operated), group 2 (TT without reperfusion) and group 3 (TT with reperfusion). TT was induced by rotating the left testis 720° for 1 h. Testicular reperfusion proceeded for 24 h. Histopathological examination, oxidative stress biomarker measurements, RNA sequencing and RT-PCR were performed. RESULTS: Testicular ischemia/reperfusion injury induced marked histopathological changes. Germ cell apoptosis was significantly increased in group 3 compared with group 1 and 2 (mean apoptotic index: 26.22 vs. 0.64 and 0.56; p = 0.024, and p = 0.024, respectively). Johnsen score in group 3 was smaller than that in group 1 and 2 (mean: 8.81 vs 9.45 and 9.47 points/tubule; p = 0.001, p < 0.001, respectively). Testicular ischemia/reperfusion injury significantly upregulated the expression of genes associated with apoptosis and antioxidant enzymes and significantly downregulated the expression of genes associated with spermatogenesis. CONCLUSION: One hour of TT followed by reperfusion injury caused histopathological testicular damage. The relatively high Johnsen score indicated spermatogenesis was maintained. Genes associated with spermatogenesis were downregulated in the TT rat model. IMPACT: How ischemia/reperfusion injury in testicular torsion (TT) affects the expressions of genes associated with spermatogenesis has not been fully elucidated. This is the first study to report comprehensive gene expression profiles using next generation sequencing for an animal model of TT. Our results revealed that ischemia/reperfusion injury downregulated the expression of genes associated with spermatogenesis and sperm function in addition to histopathological damage, even though the duration of ischemia was short.

Serum Concentrations of Infliximab and IL-6 for Predicting One-Year Discontinuation of Infliximab Treatment Owing to Secondary Non-response in Patients with Rheumatoid Arthritis.

Secondary non-response to infliximab (IFX) occurs in some patients with rheumatoid arthritis (RA). Although therapeutic drug monitoring (TDM) is a useful tool to optimize IFX therapy, it is unclear whether it can help to identify the risk of secondary non-response. This study aimed to explore the utility of serum levels of IFX or other biomarkers to predict IFX discontinuation owing to secondary non-response. A single-center, retrospective study was conducted using the Kyoto University Rheumatoid Arthritis Management Alliance cohort database between 2011 and 2020. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. An electrochemiluminescence assay was used to quantify serum levels of tumor necrosis factor-α and interleukin-6 and detect anti-drug antibodies. Eighty-four out of 310 patients were eligible for this study. The cutoff levels of biomarkers were determined by receiver operating characteristic analysis. IFX persistence was similar between groups stratified using IFX levels, tumor necrosis factor-α levels, interleukin-6 levels, and anti-drug antibodies positivity. The group with lower IFX and higher interleukin-6 levels had the worst therapy persistence (p = 0.017) and the most frequent disease worsening (90.0%, p < 0.001). Evaluating both interleukin-6 and IFX levels, not just IFX alone, enabled us to identify patients at risk of discontinuing IFX treatment. These findings support the utility of measuring IFX and interleukin-6 levels for successful maintenance therapy for RA.

Predicting dry weight change in Hemodialysis patients using machine learning.

BACKGROUND: Machine Learning has been increasingly used in the medical field, including managing patients undergoing hemodialysis. The random forest classifier is a Machine Learning method that can generate high accuracy and interpretability in the data analysis of various diseases. We attempted to apply Machine Learning to adjust dry weight, the appropriate volume status of patients undergoing hemodialysis, which requires a complex decision-making process considering multiple indicators and the patient's physical conditions. METHODS: All medical data and 69,375 dialysis records of 314 Asian patients undergoing hemodialysis at a single dialysis center in Japan between July 2018 and April 2020 were collected from the electronic medical record system. Using the random forest classifier, we developed models to predict the probabilities of adjusting the dry weight at each dialysis session. RESULTS: The areas under the receiver-operating-characteristic curves of the models for adjusting the dry weight upward and downward were 0.70 and 0.74, respectively. The average probability of upward adjustment of the dry weight had sharp a peak around the actual change over time, while the average probability of downward adjustment of the dry weight formed a gradual peak. Feature importance analysis revealed that median blood pressure decline was a strong predictor for adjusting the dry weight upward. In contrast, elevated serum levels of C-reactive protein and hypoalbuminemia were important indicators for adjusting the dry weight downward. CONCLUSIONS: The random forest classifier should provide a helpful guide to predict the optimal changes to the dry weight with relative accuracy and may be useful in clinical practice.

Efficacy of personalized exercise program on physical function in elderly patients with rheumatoid arthritis at high risk for sarcopenia: study protocol for a randomized controlled trial.

BACKGROUND: Patients with rheumatoid arthritis (RA) are prone to muscle atrophy due to inflammatory cytokines and corticosteroid use and immobility due to joint pain and deformity. Although resistance training is effective and safe in reversing muscle atrophy in RA, some patients are unable to perform a conventional high-load exercise program due to disease-related limitations. This study aims to examine the efficacy of individualized exercise therapy on physical function in elderly patients with RA who are at a high risk for sarcopenia. METHODS: This study is a single-center, parallel-group, two-arm, healthcare provider- and outcome assessor-blinded, superiority randomized controlled trial with a 1:1 allocation ratio. A total of 160 participants with RA between 60 and 85 years of age with a positive screening test for sarcopenia will be included. The intervention group will receive nutritional guidance and a four-month individualized exercise program in addition to the usual treatment. The control group will receive nutritional guidance in addition to the usual care. The primary endpoint will be physical function assessed using the Short Physical Performance Battery (SPPB) at 4 months. The data on outcome measures will be collected at baseline and at the two- and four-month follow-ups. Linear mixed-effects models for repeated measures will be conducted using the modified intention-to-treat analysis population. DISCUSSION: This study will provide evidence on whether a personalized exercise program can improve physical function and quality of life in elderly patients with RA. Some limitations include limited generalizability due to the single-center study and lack of blinding of the patients to the intervention assignment because of the nature of the exercise. Physical therapists may use this knowledge in their daily practice to improve RA treatment. Tailored exercise may enhance the health outcomes of the RA population and contribute to a reduction in healthcare costs. TRIAL REGISTRATION: The study protocol was retrospectively registered at the University hospital Medical Information Network-Clinical Trial Repository (UMIN-CTR) (registration number: UMIN000044930, https://www.umin.ac.jp/ctr/index-j.htm ) on January 4, 2022.

High plasma homocysteine level is associated with increased prevalence of the non-remission state in rheumatoid arthritis: Findings from the KURAMA cohort.

OBJECTIVES: We aimed to determine the clinical impact of plasma homocysteine levels on disease activity and clinical remission in patients with rheumatoid arthritis (RA). METHODS: A cross-sectional study was conducted using KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) database. We enrolled 291 female patients, who were treated in a treat-to-target manner. We measured plasma total homocysteine using a liquid chromatography-tandem mass spectrometry system and collected clinical data including a 28-joint RA disease activity score-erythrocyte sedimentation rate (DAS28-ESR). Clinical remission of disease activity was defined as a DAS28-ESR < 2.6. RESULTS: In a univariable analysis, the plasma homocysteine concentration was significantly and positively associated with DAS-28-ESR and was higher in the non-remission group than in the remission group. The cutoff value of the plasma homocysteine level was calculated to be 7.9 nmol/mL by the test of the receiver operating characteristic curve analysis. In a multivariable analysis, after adjusting for clinically relevant variables, the high homocysteine level remained a significant positive association for DAS28-ESR (estimate 0.27, P = .0019) and a positive factor for the presence of RA non-remission (odds ratio 2.39, P = .0071). CONCLUSIONS: Increased plasma homocysteine levels showed a significant positive association with current disease activity and the non-remission state in female patients with RA under treat-to-target treatment. The findings suggest the potential utility of plasma homocysteine as a disease state marker reflecting conditions that are treatment failure and difficult to remission and may provide clinical evidence on the interplay between homocysteine and inflammatory activation in RA.

N-terminus of Etanercept is Proteolytically Processed by Dipeptidyl Peptidase-4.

PURPOSE: Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor (TNF) receptor and the Fc portion of human immunoglobulin G1. The N-terminus of ETN has a putative sequence cleaved by dipeptidyl peptidase-4 (DPP-4). The purpose of this study was to investigate the biotransformation of ETN in humans and mice and evaluate its effects on functional properties. METHODS: An analytical method using liquid chromatography-mass spectrometry (LC-MS/MS) was established. The N-terminal heterogeneity of ETN was assessed in the serum of patients with rheumatoid arthritis or mice receiving ETN. The in vitro N-terminal truncation was explored using recombinant DPP-4. The binding affinity to TNF-α or TNF-ß was investigated using an in-house enzyme-linked immunosorbent assay. RESULTS: In the formulations, about 90% of ETN had an intact N-terminus, while the N-terminal truncated form was most abundant in the serum of the patients with rheumatoid arthritis and mice. Recombinant human DPP-4 cleaved two amino acids from the N-terminus of ETN in vitro. Sitagliptin, a DPP-4 inhibitor, inhibited N-terminal truncation both in vivo and in vitro. However, N-terminal truncation did not affect the binding ability to TNF-α or TNF-ß and the pharmacokinetics of ETN. ETN biosimilars exhibited similar characteristics to the reference product in vivo and in vitro. CONCLUSIONS: ETN undergoes N-terminal truncation in the body, and DPP-4 cleaves exogenous ETN via N-terminal proteolysis. The application of an MS-based assay will detect novel biotransformation of therapeutic proteins.

Applying the Pediatric Appendicitis Score to predict complicated appendicitis in children.

BACKGROUND: This study aimed to investigate the efficacy of the Pediatric Appendicitis Score (PAS) and other indicators to enable the prediction of complicated appendicitis (CA) in children. METHODS: This retrospective cohort study evaluated children (n = 161) aged ≤16 years with acute appendicitis between 2008 and 2020. Demographic data, symptoms, physical findings, laboratory data, and PASs were collected. Multivariate analysis was performed to identify predictors for CA. Receiver operating characteristic (ROC) curves were constructed. The diagnostic performance of each predictor was evaluated. RESULTS: Multivariate analysis identified three predictors for CA: duration of symptoms >1 day, C-reactive protein (CRP) level > 4 mg/dL, and PAS ≥ 8. The ROC curve of the combined three predictors showed an area under the curve of 0.91. The multivariate ROC curve revealed that the presence of a PAS contributed to a significant improvement in the diagnosis of CA compared to the absence of PAS. When combined, the three predictors had a high specificity of 99% and positive predictive value of 98%. CONCLUSIONS: A symptom duration >1 day, CRP > 4 mg/dL, and PAS ≥ 8 were predictors for CA. The PAS can be useful for prediction of CA when combined with the duration of symptoms, CRP, or both.

Partially hydrolyzed guar gum alleviates hepatic steatosis and alters specific gut microbiota in a murine liver injury model.

PURPOSE: The gut microbiota, via the gut-liver axis, plays an important role in the development of intestinal failure-associated liver disease. Here, we investigated whether partially hydrolyzed guar gum (PHGG), a dietary fiber could alleviate liver damage and modulate the gut microbiota in a murine liver injury (LI) model. METHODS: Liver injury was induced in 6-week-old male C57BL/6 mice using an enteral liquid diet composed of parenteral nutrition (LI group) and treated with 5% PHGG (LI/PHGG group). Liver histopathology was examined using oil red O and a tumor necrosis factor-α (TNF-α) labeling. The gut microbiota was examined using 16S rRNA gene sequencing. RESULTS: Lipid accumulation was significantly decreased in the LI /PHGG group when compared with that of the LI group. The area of TNF-α-positive cells was significantly higher in the LI group when compared with that of the control. The principal coordinate analysis (PCoA) revealed pronounced changes in the gut microbiota after PHGG treatment. Linear discriminant analysis of effect size showed that PHGG treatment significantly increased cecal abundance of Parabacteroides. CONCLUSIONS: PHGG alleviated hepatic steatosis following liver injury in mice. The protective effect of PHGG treatment could be associated with increased abundance of Parabacteroides in the cecum.

[Rapid response of secondary plasma cell leukemia after carfilzomib and dexamethasone therapy].

An 83-year-old man was admitted to our hospital due to a recurrence of multiple myeloma, accompanied by the appearance of plasma cells in the peripheral blood (PB). Subsequently, he was diagnosed with secondary plasma cell leukemia (sPCL). A chemotherapy regimen of carfilzomib and dexamethasone (Cd) combination therapy was selected, and 15 days later, plasma cells completely disappeared from the PB. Cd therapy was continued, and the free kappa chain levels normalized. Three months later, M-protein could not be detected using serum electrophoresis. This is a valuable report wherein Cd combination therapy was successful in treating sPCL.

[Novel germline SAMD9 mutation in an elderly patient with myelodysplastic syndrome].

An 80-year-old Japanese male patient presented to our hospital with complaints of fatigue. His peripheral blood tests revealed pancytopenia with predominant lymphocytes and without blasts. The bone marrow (BM) aspiration was unsuccessful due to a dry tap, and the subsequent BM biopsy revealed hypocellular marrow with fibrosis. He was diagnosed with myelodysplastic syndrome (MDS) with excess blasts (EB)-2 based on CD34-positive cells. The chromosome analysis of the BM revealed monosomy 7, and the SAMD9 W22* mutation was detected (variant allele frequency [VAF] of 51.22%) using next-generation sequencing. An identical mutation was observed in the buccal mucosa (VAF of 50%), which was confirmed as a germline mutation. The SAMD9 gene mutation is reported as one of the causative genes for MIRAGE syndrome and child-onset MDS. The present case was considered a loss-of-function mutation due to the near full-length SAMD9 deletion. This is the first adult case of MDS with SAMD9 W22* as a germline mutation.

Childhood exercise predicts response inhibition in later life via changes in brain connectivity and structure.

Participation in exercise during early life (i.e., childhood through adolescence) enhances response inhibition; however, it is unclear whether participation in exercise during early life positively predicts response inhibition in later life. This historical cohort study was designed to clarify whether participation in exercise (e.g., structured sports participation) during early life predicts response inhibition in adulthood and if so, to reveal the brain connectivity and cortical structures contributing to this association. We analyzed data derived from 214 participants (women = 104, men = 110; age: 26‒69 years). Results indicated that participation in exercise during childhood (before entering junior high school; ≤ 12 years old) significantly predicted better response inhibition. No such association was found if exercise participation took place in early adolescence or later (junior high school or high school; ≥ 12 years old). The positive association of exercise participation during childhood with response inhibition was moderated by decreased structural and functional connectivity in the frontoparietal (FPN), cingulo-opercular (CON), and default mode networks (DMN), and increased inter-hemispheric structural networks. Greater cortical thickness and lower levels of dendritic arborization and density in the FPN, CON, and DMN also moderated this positive association. Our results suggest that participation in exercise during childhood positively predicts response inhibition later in life and that this association can be moderated by changes in neuronal circuitry, such as increased cortical thickness and efficiency, and strengthened inter-hemispheric connectivity.

Stapled versus hand-sewn intestinal anastomosis in pediatric patients: a systematic review and meta-analysis.

BACKGROUND: The safety and feasibility of stapled intestinal anastomosis have been widely reported in adults. However, the efficacy of stapled anastomosis (SA) in children is unclear. The aim of this study was to perform a systematic review and meta-analysis to evaluate the safety and effectiveness of SA compared with hand-sewn anastomosis (HA) in pediatric patients. METHODS: A systematic literature search was performed using PubMed, the Cochrane Library, and Scopus databases. Studies comparing outcomes of children aged < 7 years and subgroups of children aged < 1 year who underwent SA or HA were included. Primary outcomes were anastomotic leakage and anastomotic stricture. Mean differences (MDs) with 95 % confidence intervals (CIs) were calculated for continuous variables. Odds ratios (ORs) with 95 % CIs were calculated for dichotomous variables. Interstudy heterogeneity was assessed using the chi-squared test and was quantified using the I² statistic. RESULTS: One randomized control trial and five retrospective cohort studies, comprising 633 cases (229 SA cases and 404 HA cases), were included. No significant differences were observed in anastomotic leakage (6.5 % vs. 7.4 %; OR, 0.93; 95 % CI, 0.37-2.34; p = 0.88), anastomotic stricture (4.1 % vs. 9.3 %; OR, 0.54; 95 % CI, 0.19-1.51; p = 0.24), ileus (7.1 % vs. 9.3 %, OR, 2.35; 95 % CI, 0.15-37.51; p = 0.54), anastomosis-related complications (9.5 % vs. 10.9 %, OR, 0.98; 95 % CI, 0.52-1.86; p = 0.96; I2 = 39 %), and time until full-feeding (MD = -3.57 days; 95 % CI, -11.36 to 4.23; p = 0.37) between SA and HA. Operative time was significantly shorter in SA than in HA in children aged < 1 year (MD = -20.36 min; 95 % CI, -26.13 to -14.59). CONCLUSIONS: SA required shorter operative time and was comparable to HA in the overall complication rate. Although the evidence was insufficient, SA could be an option for intestinal anastomosis in children.

[Successful steroid pulse therapy for COVID-19 associated respiratory failure initially mimicking bortezomib-induced lung injury].

From December 2019, a 71-year-old male underwent three cycles of a combination therapy of pomalidomide, bortezomib, and dexamethasone for relapsed multiple myeloma and a very good partial response was achieved. In March 2020, he developed a fever of 38.9°C and computed tomography revealed bilateral ground-glass opacities. Antibiotic therapy was ineffective. Bronchoscopy was performed and bortezomib-induced lung injury was initially suspected. Due to respiratory exacerbation, high-dose steroid therapy was administered, which resulted in a dramatic improvement of the patient's respiratory failure. Thereafter, reverse transcription polymerase chain reaction performed on a preserved bronchial lavage sample tested positive, and thus his diagnosis was corrected to COVID-19 pneumonia. It is difficult to discriminate COVID-19 pneumonia from drug-induced lung disease, as both disorders can present similar ground-glass opacities on computed tomography. Therefore, with this presented case, we summarize our experience with steroid therapy for COVID-19 associated respiratory distress at our institution.

Suprarenal fixation is associated with worse midterm renal function after endovascular abdominal aortic aneurysm repair compared with infrarenal fixation.

BACKGROUND: Several reports have indicated that suprarenal (SR) fixation may impair renal function after endovascular abdominal aortic aneurysm repair (EVAR). However, most were short-term or at most, 1-year observational studies; therefore, the midterm effects on renal function remain unclear. This study aimed to identify predictors of midterm renal dysfunction after EVAR and compare renal outcomes in patients after EVAR with SR and infrarenal (IR) fixation. METHODS: A total of 467 patients who underwent EVAR of nonruptured IR abdominal aortic aneurysm between 2007 and 2014 were reviewed in a prospectively collected database. Patients on hemodialysis at baseline were excluded. Among the remaining patients, those with 3-year laboratory testing were included in this study. Patients who developed acute kidney injury were excluded from the late renal function estimation. Predictors of 3-year renal function decline were estimated using logistic regression analysis. In addition, patients undergoing EVAR with IR (IR group) and SR fixation devices (SR group) were propensity matched by age, sex, baseline renal function, baseline aneurysm diameter, comorbidities, smoking habits, and regular use of medicines that may act on kidney function. Changes in renal function after surgery were compared between the IR group and the SR group. RESULTS: During the study period, 237 patients (102 IRs and 135 SRs) were followed up with laboratory testing 3 years after surgery. Logistic regression analysis revealed that the use of a SR fixation device was independently predictive of a more than 20% decrease in the estimated glomerular filtration rate at 3 years after EVAR (odds ratio, 2.06; 95% confidence interval, 1.18-3.58; P = .011). Eleven patients who developed acute kidney injury (1 IR and 10 SRs) were excluded from the subsequent analysis. After propensity score matching, 87 pairs were selected (mean age, 77.2 ± 6.3 years; 151 males [86.8%]). The mean follow-up duration was 5.5 ± 1.8 years. In the SR group, estimated glomerular filtration rate at 3 years after surgery decreased significantly more than that in the IR group (mean of 17.8% vs 11.6%, respectively; P = .034). CONCLUSIONS: This study suggests that, compared with EVAR with IR endograft fixation, EVAR with SR endograft fixation is associated with worse outcomes for midterm renal function.

Aneurysm Sac Thrombus Volume Predicts Aneurysm Expansion with Type II Endoleak After Endovascular Aneurysm Repair.

BACKGROUND: Several studies have analyzed risk factors that may influence the incidence of type II endoleak with sac expansion after endovascular aneurysm repair (EVAR). However, the impact of intraluminal thrombus volume on the incidence of sac expansion with type II endoleak requires further analysis. This study examined the correlation between preoperative intraluminal thrombus and the incidence of type II endoleak and late sac expansion by measuring the thrombus volume. METHODS: Between June 2007 and March 2014, 423 patients underwent EVAR at our institution. Two hundred and eighty patients with preoperative and postoperative computed tomography angiography (CTA) were included in this study. Data were collected prospectively and supplemented with a retrospective review of the medical records and radiologic images, and demographic and clinical characteristic profiles were collected. Logistic regression and Cox regression analyses were used to assess each variable's association with the incidences of persistent or new endoleak and sac expansion. RESULTS: Of the 280 patients, 46.7% (131 patients) had persistent type II endoleak, and 19.6% (55 patients) had persistent type II endoleak with significant sac expansion (≥5 mm). The mean follow-up duration was 60 months (interquartile range, 24-72 months). Cox regression analysis showed that older age (P = 0.001), intraluminal thrombus volume ratio (thrombus volume [T vol]/aortic aneurysm volume [A vol]) (P = 0.042) and IMA diameter (P = 0.004) were significant predictors of the incidence of sac expansion with persistent or new type II endoleak. The receiver operating characteristic curve analysis revealed a cutoff of 51% T vol/A vol (area under the curve [AUC]: 0.59) and 2.9 mm (area under the curve [AUC]: 0.60). The rate of freedom from sac expansion (≥5 mm) during followup was significantly higher in patients with ≥51% T vol/A vol than in those with a lower T vol/A vol (P = 0.010). CONCLUSIONS: Preoperative sac thrombus volume, IMA diameter, and older age predict the incidence of aneurysm expansion with type II endoleak after EVAR.

Usefulness of the pediatric appendicitis score for assessing the severity of acute appendicitis in children.

BACKGROUND: We investigated relationships between the Pediatric Appendicitis Score (PAS) and pathological progression and disease severity in pediatric acute appendicitis. METHODS: We retrospectively evaluated 72 children who underwent surgery for acute appendicitis. We divided them into groups: simple appendicitis (n = 28) or complicated appendicitis (n = 44). We compared the influence of age, body temperature, blood test findings, hospitalization period, number of complications, and PAS between the groups. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value of the PAS for diagnosing complicated appendicitis. A receiver operating characteristic curve was constructed to evaluate the cut-off value for diagnosing complicated appendicitis. To assess the severity of acute appendicitis, we divided the patients into groups according to that cut-off value. RESULTS: There were statistically significant differences in the PAS between simple appendicitis and complicated appendicitis (5.8 versus 7.9). The receiver operating characteristic curve indicated a PAS cut-off value of 8. A PAS ≥ 8 had a sensitivity of 73%, a specificity of 89%, a positive predictive value of 91%, and a negative predictive value of 68%. A PAS ≥ 8 was associated with significantly longer hospitalization and more complications than a PAS < 8. CONCLUSIONS: The PAS may be associated with pathological progression and disease severity in appendicitis.

Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor 1 Predicts the Changes of Rheumatoid Factor Titers in Rheumatoid Arthritis.

OBJECTIVE: The aim of this longitudinal study was to examine the clinical significance of soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) in patients with rheumatoid arthritis. METHODS: We gathered demographic and clinical data for a large rheumatoid arthritis cohort at 3 time points. Blood samples were collected at each time point; the number of samples was 282 cases in 2012, 431 cases in 2013, and 500 cases in 2014. Plasma sLOX-1 was measured by enzyme-linked immunosorbent assay. Correlations between sLOX-1 and clinical data were analyzed. Predictive factors associated with changes in sLOX-1 and rheumatoid factor (RF) were analyzed by multivariate linear regression. RESULTS: Plasma sLOX-1 level was significantly correlated with RF titer and other clinical parameters. The longitudinal analyses showed that changes in sLOX-1 were significantly correlated with changes in RF titers and with those at baseline. Multivariate linear regression analysis revealed that changes in RF and baseline RF were predictive factors for changes in sLOX-1. Conversely, the changes in RF were significantly correlated with the changes in sLOX-1 in all years. A stepwise regression analysis showed that the change in sLOX-1 was a predictive factor for the change in RF. CONCLUSIONS: The change in sLOX-1 has predictive value for assessing the change in RF, indicating the usefulness of sLOX-1 in clinical practice.

A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain.

OBJECTIVE: To identify novel autoantibodies for neuropathic pain (NeP). METHODS: We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens. RESULTS: Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p < 0.05). These autoantibodies were all from the IgG2 subclass and colocalized mostly with isolectin B4- and P2X3-positive pain-conducting small neurons but not with S100ß-positive myelinated neurons. WB revealed a common immunoreactive band (approximately 220kDa). IP and LC-MS/MS studies identified plexin D1 as a target autoantigen. Immunoadsorption tests with recombinant human plexin D1 in IFA revealed that all 11 anti-small DRG neuron antibody-positive patients had anti-plexin D1 antibodies. Application of anti-plexin D1 antibody-positive patient sera to cultured DRG neurons increased membrane permeability, leading to cellular swelling. NeP patients with anti-plexin D1 antibodies commonly developed burning pain and current perception threshold abnormalities for C-fibers. Main comorbidities were atopy and collagen-vascular disease. Immunotherapies ameliorated NeP in 7 treated cases. INTERPRETATION: Anti-plexin D1 antibodies are a novel biomarker for immunotherapy-responsive NeP. Ann Neurol 2018;84:208-224.