Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Proteomics associated with coronary high-risk plaques by optical coherence tomography.

Biomarkers are widely used for the diagnosis and monitoring of cardiovascular disease. However, markers for coronary high-risk plaques have not been identified. The aim of this study was to identify proteins specific to coronary high-risk plaques. Fifty-one patients (71.2 ± 11.1 years, male: 66.7%) who underwent intracoronary optical coherence tomography imaging and provided blood specimens for proteomic analysis were prospectively enrolled. A total of 1470 plasma proteins were analyzed per patient using the Olink® Explore 1536 Reagent Kit. In patients with thin-cap fibroatheroma, the protein expression of Calretinin (CALB2), Corticoliberin (CRH) and Alkaline phosphatase, placental type (ALPP) were significantly increased, while the expression of Neuroplastin (NPTN), Folate receptor gamma (FOLR3) and Serpin A12 (SERPINA12) were significantly decreased. In patients with macrophage infiltration, the protein expressions of Fatty acid-binding protein, intestinal (FABP2), and Fibroblast growth factor 21 (FGF21) were significantly decreased. In patients with lipid-rich plaques, the protein expression of Interleukin-17 C (IL17C) was significantly increased, while the expression of Fc receptor-like protein 3 (FCRL3) was significantly decreased. These proteins might be useful markers in identifying patients with coronary high-risk plaques. Clinical Trial Registration: https://www.umin.ac.jp/ctr/ , UMIN000041692.

Acute respiratory failure caused by brainstem demyelinating lesions in an older patient with an atypical relapsing autoimmune disorder.

An 84-year-old man presented with somnolence, dysphagia, and right hemiplegia, all occurring within a month, approximately one year after initial admission due to subacute, transient cognitive decline suggestive of acute disseminated encephalomyelitis involving the cerebral white matter. Serial magnetic resonance imaging (MRI) studies over that period revealed three high-intensity signal lesions on fluid-attenuated inversion recovery images, appearing in chronological order in the left upper and left lower medulla oblongata and left pontine base. Despite some clinical improvement following methylprednisolone pulse therapy, the patient died of respiratory failure. Autopsy revealed four fresh, well-defined lesions in the brainstem, three of which corresponded to the lesions detected radiologically. The remaining lesion was located in the dorsal medulla oblongata and involved the right solitary nucleus. This might have appeared at a later disease stage, eventually causing respiratory failure. Histologically, all four lesions showed loss of myelin, preservation of axons, and infiltration of lymphocytes, predominantly CD8-positive T cells, consistent with the histological features of autoimmune demyelinating diseases, particularly the confluent demyelination observed in the early and acute phases of multiple sclerosis (MS). In the cerebral white matter, autoimmune demyelination appeared superimposed on ischemic changes, consistent with the cerebrospinal fluid (CSF) and MRI findings on initial admission. No anti-AQP4 or MOG antibodies or those potentially causing autoimmune encephalitis/demyelination were detected in either the serum or CSF. Despite several similarities to MS, such as the relapsing-remitting disease course and lesion histology, the entire clinicopathological picture in the present patient, especially the advanced age at onset and development of brainstem lesions in close proximity within a short time frame, did not fit those of MS or other autoimmune diseases that are currently established. The present results suggest that exceptionally older individuals can be affected by an as yet unknown inflammatory demyelinating disease of the CNS.

Layered plaque and plaque volume in patients with acute coronary syndromes.

BACKGROUND: Layered plaque is a signature of previous subclinical plaque destabilization and healing. Following plaque disruption, thrombus becomes organized, resulting in creation of a new layer, which might contribute to rapid step-wise progression of the plaque. However, the relationship between layered plaque and plaque volume has not been fully elucidated. METHODS: Patients who presented with acute coronary syndromes (ACS) and underwent pre-intervention optical coherence tomography (OCT) and intravascular ultrasound (IVUS) imaging of the culprit lesion were included. Layered plaque was identified by OCT, and plaque volume around the culprit lesion was measured by IVUS. RESULTS: Among 150 patients (52 with layered plaque; 98 non-layered plaque), total atheroma volume (183.3 mm3[114.2 mm3 to 275.0 mm3] vs. 119.3 mm3[68.9 mm3 to 185.5 mm3], p = 0.004), percent atheroma volume (PAV) (60.1%[54.7-60.1%] vs. 53.7%[46.8-60.6%], p = 0.001), and plaque burden (86.5%[81.7-85.7%] vs. 82.6%[77.9-85.4%], p = 0.001) were significantly greater in patients with layered plaques than in those with non-layered plaques. When layered plaques were divided into multi-layered or single-layered plaques, PAV was significantly greater in patients with multi-layered plaques than in those with single-layered plaques (62.1%[56.8-67.8%] vs. 57.5%[48.9-60.1%], p = 0.017). Layered plaques, compared to those with non-layered pattern, had larger lipid index (1958.0[420.9 to 2502.9] vs. 597.2[169.1 to 1624.7], p = 0.014). CONCLUSION: Layered plaques, compared to non-layered plaques, had significantly greater plaque volume and lipid index. These results indicate that plaque disruption and the subsequent healing process significantly contribute to plaque progression at the culprit lesion in patients with ACS. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov , NCT01110538, NCT03479723, UMIN000041692.

The estimation of coronary artery calcium thickness by computed tomography angiography based on optical coherence tomography measurements.

Optical coherence tomography (OCT) is recommended to be the most appropriate modality in assessing calcium thickness, however, it has limitations associated with infrared attenuation. Although coronary computed tomography angiography (CCTA) detects calcification, it has low resolution and hence not recommended to measure the calcium size. The aim of this study was to devise a simple algorithm to estimate calcium thickness based on the CCTA image. A total of 68 patients who had CCTA for suspected coronary artery disease and subsequently went on to have OCT were included in the study. 238 lesions of them divided into derivation and validation dataset at 2:1 ratio (47 patients with 159 lesions and 21 with 79, respectively) were analyzed. A new method was developed to estimate calcium thickness from the maximum CT density within the calcification and compared with calcium thickness measured by OCT. Maximum Calcium density and measured calcium-border CT density had a good correlation with a linear equation of y = 0.58x + 201 (r = 0.892, 95% CI 0.855-0.919, p < 0.001). The estimated calcium thickness derived from this equation showed strong agreement with measured calcium thickness in validation and derivation dataset (r2 = 0.481 and 0.527, 95% CI 0.609-0.842 and 0.497-0.782, p < 0.001 in both, respectively), more accurate than the estimation by full width at half maximum and inflection point method. In conclusion, this novel method provided the estimation of calcium thickness more accurately than conventional methods.

Potent platelet inhibition with peri-procedural tirofiban may attenuate progression of atherosclerosis in patients with acute coronary syndromes.

Organization of platelet-rich thrombus at the site of plaque disruption may contribute to rapid progression of atherosclerosis. This study was conducted to investigate if potent platelet inhibition therapy in patients with acute coronary syndromes (ACS) mitigates plaque progression. Patients enrolled in the EROSION study who presented with ACS caused by plaque erosion and underwent serial imaging of the culprit lesion by optical coherence tomography at baseline, 1 month, and 1 year were included. Among 49 patients, 32 (65.3%) patients were treated with glycoprotein IIb/IIIa inhibitor (GPI) in addition to aspirin and ticagrelor. The increase in area stenosis from baseline to 1-year follow-up was significantly smaller in patients treated with GPI, compared to those without GPI therapy (4.8% [- 1.6 to 10.9] vs. 9.6% [4.0 to 21.3], p = 0.031). The cohort was divided into 2 groups based on culprit lesion phenotype at 1 year: Group A, new layer formation at 1-year that was not present at baseline (n = 18); Group B, no new layer formation (n = 31). A new layer was less frequently found at 1 year in patients treated with GPI than in those without GPI (25.0% vs. 58.8%, p = 0.019). Group A, compared to Group B, was associated with a greater increase in area stenosis (19.0 ± 16.4% vs. 3.7 ± 7.1%; p < 0.001). Potent platelet inhibition with GPI in patients with ACS caused by plaque erosion was associated with lower incidence of new layer formation and less plaque progression.

Biomarkers associated with coronary high-risk plaques.

Vascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary high-risk plaques defined according to intravascular imaging have not been systematically studied. A total of 69 patients with coronary artery disease who underwent both optical coherence tomography and intravascular ultrasound imaging, and who provided blood specimens were included. Comprehensive biomarkers for inflammation, lipid, and coagulation were analyzed. Composite models sought biomarker patterns associated with thin-cap fibroatheroma (TCFA) and "high-risk plaques" (TCFA and large plaque burden). Two different composite models were developed for TCFA, based on the finding that high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1, fibrinogen, IL-6, homocysteine and amyloid A levels were elevated, and high-density lipoprotein cholesterol (HDL) and bile acid levels were decreased in these patients. Both composite models were highly accurate for detecting patients with TCFA (area under curve [AUC]: 0.883 in model-A and 0.875 in model-B, both p < 0.001). In addition, creatinine, hsCRP, fibrinogen, tumor necrosis factor-α, IL-6, homocysteine, amyloid A, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques". Two composite models were highly accurate for detection of patients with "high-risk plaques" (AUC: 0.925 in model-A and 0.947 in model-B, both p < 0.001). Biomarkers useful for detection of patients with high-risk coronary plaques defined according to intravascular imaging have been identified. These biomarkers may be useful to risk stratify patients and to develop targeted therapy.Clinical Trial Registration https://www.umin.ac.jp/ctr/ , UMIN000041692. Biomarkers and high-risk plaques hsCRP, PAI-1, fibrinogen, IL-6, homocysteine, amyloid A, HDL, and bile acid were useful for detecting patients with TCFA. hsCRP, fibrinogen, IL-6, homocysteine, amyloid A, creatinine, TNFα, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques" (plaque which has both TCFA and large plaque burden). White arrowhead denotes TCFA. Red and green dashed lines denote lumen area and external elastic membrane area, respectively.

Serum uric acid control for prevention of gout flare in patients with asymptomatic hyperuricaemia: a retrospective cohort study of health insurance claims and medical check-up data in Japan.

OBJECTIVES: In patients with gout, treating to target serum uric acid levels (sUA) of ≤6.0 mg/dL is universally recommended to prevent gout flare. However, there is no consensus on asymptomatic hyperuricaemia. Using Japanese health insurance claims data, we explored potential benefits of sUA control for preventing gout flare in subjects with asymptomatic hyperuricaemia. METHODS: This retrospective cohort study analysed the JMDC Claims Database from April 2012 through June 2019. Subjects with sUA ≥8.0 mg/dL were identified, and disease status (prescriptions for urate-lowering therapy (ULT), occurrence of gout flare, sUA) was investigated for 1 year. Time to first onset and incidence rate of gout flare were determined by disease status subgroups for 2 years or more. The relationship between gout flare and sUA control was assessed using multivariable analysis. RESULTS: The analysis population was 19 261 subjects who met eligibility criteria. We found fewer occurrences of gout flare, for both gout and asymptomatic hyperuricaemia, in patients who achieved sUA ≤6.0 mg/dL with ULT than in patients whose sUA remained >6.0 mg/dL or who were not receiving ULT. In particular, analysis by a Cox proportional-hazard model for time to first gout flare indicated that the HR was lowest, at 0.45 (95% CI 0.27 to 0.76), in subjects with asymptomatic hyperuricaemia on ULT (5.0

Comparison of post-stent optical coherence tomography findings: Layered versus non-layered culprit lesions.

OBJECTIVES: This study aimed to investigate the vascular response of lesions with a layered phenotype. BACKGROUND: Recent studies have shown that layered plaques at culprit lesions detected by optical coherence tomography (OCT) have greater plaque burden and more inflammatory features than non-layered plaques. METHODS: This is a retrospective observational study. A total of 193 target lesions from 193 patients [100 patients with acute coronary syndromes (ACS) and 93 with stable angina pectoris (SAP)] who had undergone OCT imaging of the culprit lesion both before and after stenting were included. Layered plaques were identified by OCT as plaques with layers of different optical density. Patients were divided into two groups based on the presence or absence of a layered phenotype at the culprit lesion, and pre- and post-procedure OCT findings were compared. RESULTS: Among 193 patients, 36 (36.0%) lesions in ACS patients and 56 (60.2%) lesions in SAP patients were found to have a layered phenotype at the culprit lesion. At baseline, percent area stenosis was greater in layered plaque than in non-layered plaque (p = .019). Following stent implantation, the stent expansion ratio and mean stent eccentricity index were significantly lower in layered plaques than in non-layered plaques (p = .041, p = .017, respectively), mainly derived from ACS patients. CONCLUSION: Following stent implantation, plaques with a layered phenotype had less stent expansion and more eccentric lumens. Aggressive balloon dilation may be required to obtain optimal stent outcomes in patients with a layered plaque phenotype at the culprit lesion.

Comparison of post-stent optical coherence tomography findings among three subtypes of calcified culprit plaques in patients with acute coronary syndrome.

OBJECTIVES: To compare the postprocedural optical coherence tomography (OCT) findings and in-hospital outcomes among the three subtypes of calcified plaques: eruptive calcified nodules, superficial calcific sheet, and calcified protrusion. BACKGROUND: Recently, three subtypes of calcified culprit plaques were reported in patients with acute coronary syndrome (ACS). How these subtypes respond to stenting is unknown. METHODS: ACS patients with calcified plaque at the culprit lesion were selected from our database. OCT findings at baseline and after stent implantation were compared. RESULTS: In the final analysis, 87 cases were included. Preprocedural OCT showed eruptive calcified nodules in 19 (21.8%) cases, superficial calcific sheet in 63 (72.4%), and calcified protrusion in 5 (5.7%). Stent edge dissection (SED) and incomplete stent apposition (ISA) were frequently observed in the eruptive calcified nodules group compared to superficial calcific sheet or calcified protrusion (SED; 47.4% vs. 17.5% vs. 20.0%; p = .032, ISA; 94.7% vs. 58.7% vs. 0.0%; p < .001). The superficial calcific sheet group had the smallest minimal stent area (MSA) among the three groups (eruptive calcified nodules vs. superficial calcific sheet vs. calcified protrusion: 6.29 ± 2.41 vs. 4.72 ± 1.37 vs. 6.56 ± 1.13; p = .007). The superficial calcific sheet group had a higher rate of periprocedural myocardial infarction compared to the eruptive calcified nodules group (60.3% vs. 31.6%; p = .028). CONCLUSIONS: This study demonstrated eruptive calcified nodules are associated with higher incidence of SED and ISA, whereas superficial calcific sheets are associated with small MSA and higher periprocedural myocardial infarction.

The Impact of Aortic Valvular Calcium on Transcatheter Heart Valve Distortion.

OBJECTIVES: To investigate the relationship between the eccentric calcification of aortic valve and transcatheter heart valve (THV) distortion and the impact of THV distortion on echo parameters and clinical outcomes. BACKGROUND: The effects of eccentric calcification of the aortic valve on the THV distortion and the relationship between THV distortion and clinical impact were not fully understood. METHODS: Patients with symptomatic severe aortic stenosis who were undergoing THV implantation were enrolled. Patients underwent preprocedural, postprocedural multislice computed tomography (MSCT), and follow-up transthoracic echocardiogram (TTE). Delta calcium score (ΔCS) is defined as the difference between the maximum and minimal calcium scores of the three cusps, while valve distortion score (VDS) is defined as the difference between the longest and shortest stent frame, as obtained using MSCT. Patients were divided into two groups according to ΔCS: "noneccentric calcification group" and "eccentric calcification group." RESULTS: A total of 118 patients were enrolled (59 patients in noneccentric and 59 in eccentric calcification groups). VDS was significantly lower in the noneccentric calcification group than in the eccentric calcification group (1.31 ± 0.82 mm vs. 1.73 ± 0.76 mm, p=0.004). VDS was not associated with the degree of paravalvular leak (PVL) and aortic valvular mean pressure gradient (AVPG) at 30-day and 1-year follow-up TTE and the cumulative rates of all-cause death and rehospitalization at 2-year clinical follow-up. CONCLUSIONS: Eccentric valvular calcification was associated with longitudinal THV distortion. However, THV distortion was not associated with PVL, AVPG, and adverse clinical events during midterm follow-up.

Factors associated with achieving target serum uric acid level and occurrence of gouty arthritis: A retrospective observational study of Japanese health insurance claims data.

PURPOSE: This study assessed factors associated with achieving target serum uric acid (sUA) level and occurrence of gouty arthritis in Japanese clinical practice. METHODS: Japanese health insurance claims and medical check-up data from October 2015 to March 2017 were analyzed to assess factors associated with target sUA achievement in gout and asymptomatic hyperuricemia and gouty arthritis in gout. Target sUA was further assessed by subgroup analysis of urate-lowering therapy (ULT) prescriptions and outcomes, stratified by renal function. RESULTS: Patients achieving target sUA tended toward older, female, higher ULT dose, higher adherence, more comorbidities, and/or antidiabetic drugs prescribed. Renal dysfunction and/or diuretic prescriptions were associated with reduced achievement of target sUA. Severe renal dysfunction was particularly influential (odds ratio [OR] = 0.22 [95% confidence interval (CI): 0.10-0.48] for <15, 0.15 [0.10-0.23] for ≥15 to <30, compared with eGFR ≥90 mL/min/1.73 m2 ). Across all renal function categories, mean prescribed ULT dose was low (febuxostat 17.0-21.0 mg/day, allopurinol 123.1-139.6 mg/day), and target sUA achievement was reduced among renal dysfunction patients. Gouty arthritis was more likely in patients with a prior history of such occurrences, and less likely for higher ULT adherence, sUA monitored regularly at medical facilities, and/or more comorbidities. CONCLUSION: In a real-world setting, severe renal dysfunction is the most important risk factor for failure to achieve the target sUA, suggesting suboptimal disease management in patients with gout or hyperuricemia complicated by this condition. Findings associated with gouty arthritis suggest that these occurrences could be successfully managed by regular monitoring of sUA and closer adherence to ULT.

Degree of luminal narrowing and composition of thrombus in plaque erosion.

As the degree of luminal narrowing increases, shear stress increases, and high shear stress is known to activate platelets. However, the relationship between the degree of luminal narrowing and the composition of thrombus in patients with plaque erosion has not been studied. A total of 148 patients with plaque erosion and thrombus detected by optical coherence tomography were divided into tertiles based on the minimum lumen area (MLA) at the culprit lesion. Thrombus was categorized as platelet-rich or fibrin-rich. Among 148 patients, 50 (34%) were in the mild stenosis group, 49 (33%) were in the moderate stenosis group, and 49 (33%) were in the severe stenosis group. The composition of thrombus was significantly different among the 3 groups (prevalence of platelet-rich thrombus was 60% in the mild stenosis group; 78% in the moderate stenosis group; and 84% in the severe stenosis group; P = 0.021). The pattern of fibrin-rich thrombus showed the opposite: 40%, 22%, and 16%, respectively. In the multivariate analysis, current smoking was independently associated with fibrin-rich thrombus (odds ratio [OR] 2.364 [95% CI 1.004-5.567], P = 0.049). This study demonstrated that platelet-rich thrombus was the predominant type of thrombus in plaque erosion. The prevalence of fibrin-rich thrombus was highest in the mild stenosis group.

Determinants of ST-segment elevation myocardial infarction as clinical presentation of acute coronary syndrome.

Antiplatelet agents and statin therapies are widely used in patients with known cardiovascular disease. Plaque rupture (PR) and plaque erosion (PE) are the most frequent underlying mechanisms of acute coronary syndromes (ACS). The conditions and medications that are associated with ST-segment elevation myocardial infarction (STEMI) following PR or PE have not been systematically studied. A total of 838 ACS patients (494 with STEMI, 344 with NSTE-ACS) who were diagnosed with PR or PE by optical coherence tomography were included. The patients were categorized into two groups based on underlying pathology, and the baseline characteristics and culprit plaque morphology associated with STEMI were investigated within each group. Among 838 patients, 467 (55.7%) had PR, and 371 (44.3%) were diagnosed with PE. Among patients with PR, older age, hyperlipidemia, no antiplatelet therapy, higher level of low-density lipoprotein cholesterol, and greater lipid burden and macrophage infiltration were associated with increased probability of STEMI. Among patients with PE, no dual antiplatelet therapy and no statin therapy were associated with increased probability of STEMI. The incidence of STEMI caused by PR was significantly lower on antiplatelet therapy (P < 0.001), and the incidence of STEMI caused by PE was significantly lower on antiplatelet therapy (P < 0.001) or on statin therapy (P < 0.001). Antiplatelet therapy is associated with lower probability of STEMI, regardless of underlying pathology, and statin therapy is associated with lower probability of STEMI in PE as clinical presentation of ACS. Statin therapy prior to the onset of acute coronary syndromes (ACS) may reduce the probability of plaque rupture. Antiplatelet therapy prior to the onset of ACS is associated with reduced probability of ST-segment elevation myocardial infarction (STEMI) following both plaque rupture and plaque erosion, and dual antiplatelet therapy offers additional protection compared to a single antiplatelet agent in plaque erosion. The combination of statin and antiplatelet therapy may have an additive effect on reducing the probability of STEMI caused by plaque erosion. Yellow: lipid pool(necrotic core); red: fibrin-rich thrombus; gray; platelet-rich thrombus.

Circadian variations in pathogenesis of ST-segment elevation myocardial infarction: an optical coherence tomography study.

Previous studies have reported a circadian variation in the onset of ST-segment elevation myocardial infarction (STEMI). However, underlying mechanisms for the circadian variation have not been fully elucidated. We investigated the relationship between onset of STEMI and the underlying pathology using optical coherence tomography (OCT). Patients with a diagnosis of STEMI were selected from a multicenter OCT registry. Patients were divided into 4 groups based on the estimated time of onset (00:00-05:59, 06:00-11:59, 12:00-17:59, or 18:00-23:59). Underlying pathologies of MI (plaque rupture, plaque erosion, and calcified plaque) were compared among the 4 groups. Among 648 patients, plaque rupture was diagnosed in 386 patients (59.6%), plaque erosion in 197 patients (30.4%), and calcified plaque in 65 patients (10.0%). A marked circadian variation was detected in the incidence of plaque rupture with a peak at 09:00, whereas it was not evident in plaque erosion or calcified plaque. The probability of plaque rupture significantly increased in the periods of 06:00-11:59 [odds ratio (OR) 2.13, 95% confidence interval (CI) 1.30-3.49, p = 0.002] and 12:00-17:59 (OR 2.10, 95% CI 1.23-3.58, p = 0.005), compared to the period of 00:00-05:59. This circadian pattern was observed only during weekdays (p = 0.010) and it was not evident during the weekend (p = 0.742). Plaque rupture occurred most frequently in the morning and this circadian variation was evident only during weekdays. Acute MI caused by plaque rupture may be related to catecholamine surge.

Urate-lowering therapy for gout and asymptomatic hyperuricemia in the pediatric population: a cross-sectional study of a Japanese health insurance database.

BACKGROUND: Our previous research showed that uric acid lowering therapy (ULT) for gout and hyperuricemia is being prescribed for pediatric patients even though these drugs have not been approved for use in children. However, the actual clinical situation has not been clearly elucidated. In this paper, we provide an in-depth look at the details of actual clinical practice. METHODS: This retrospective cross-sectional study accessed health insurance data for 696,277 children from April 2016 through March 2017 to identify pediatric patients with gout or asymptomatic hyperuricemia, calculate the proportion of patients prescribed ULTs, and analyze population characteristics. Adherence and mean dose for febuxostat and allopurinol, the most commonly prescribed drugs, were also analyzed. RESULTS: Among children with gout or asymptomatic hyperuricemia, we found that 35.1% (97/276) were prescribed ULT. This proportion increased with age, especially among males. By comorbidity, ULT was prescribed to 47.9% (46/96) of patients with kidney disease, 41.3% (26/63) for cardiovascular disease, 40.0% (6/15) for Down syndrome, and 27.1% (32/118) for metabolic syndrome. In patients with kidney disease, febuxostat was prescribed more than twice as frequently as allopurinol (28 vs. 12). Median values for the medication possession ratio (MPR) of febuxostat and allopurinol were 70.1 and 76.7%, respectively, and prescriptions were continued for a relatively long period for both drugs. Both drugs were prescribed at about half the adult dose for patients 6-11 years old and about the same as the adult dose for patients 12-18 years old. CONCLUSIONS: This study showed that the continuous management of serum uric acid is being explored using off-label use of ULT in pediatric patients with gout or asymptomatic hyperuricemia in Japan. Drug selection is based on patient characteristics such as sex, age, and comorbidities, and pediatric dosage is based on usage experience in adults. To develop appropriate pediatric ULT, clinical trials are needed on the efficacy and safety of ULT in the pediatric population. TRIAL REGISTRATION: UMIN000036029 .

Real-world treatment of gout and asymptomatic hyperuricemia: A cross-sectional study of Japanese health insurance claims data.

OBJECTIVES: To assess gout and asymptomatic hyperuricemia in Japan and review treatment conditions. METHODS: This retrospective cross-sectional study analyzed the prevalence of hyperuricemia and gout, and characteristics and treatment of patients with those conditions, using Japanese health insurance claims and medical check-up data collected from April 2016 through March 2017. RESULTS: Among 2,531,383 persons registered in the database, 1.1% (men 1.9%, women <0.1%) were diagnosed with gout and 2.6% (4.1%, 0.4%) with asymptomatic hyperuricemia. Medical check-ups showed 13.4% (19.6%, 1.0%) of patients with hyperuricemia (serum uric acid [sUA] > 7.0 mg/dL). Urate-lowering therapy (ULT) was prescribed for 80.7% of patients identified with gout and 72.4% identified with asymptomatic hyperuricemia. ULT adherence was satisfactory, but most patients were treated with low-dose ULT. Less than half of patients receiving ULT achieved the sUA target (≤6.0 mg/dL). In gout patients, the incidence of gout flare was 47.8% (0.74 flares/person-year). CONCLUSIONS: Although hyperuricemia prevalence is similar in Japan and worldwide, gout is comparatively rare in Japan. Gout and asymptomatic hyperuricemia are often treated with low-dose ULT, and many patients fail to reach target sUA, suggesting that gout management is suboptimal in Japan. Patients would benefit from stricter focus on a treat-to-target approach for gout management.

[Tumefactive demyelinating lesion (TDL)].

Tumefactive demyelinating lesion(TDL)is defined as a large lesion, size >2 cm, mass effect, perilesional edema and/or ring enhancement. TDL could occur in multiple sclerosis(MS), neuromyelitis optica spectrum disorder(NMOSD), acute disseminated encephalomyelitis(ADEM)or other immunological diseases. Non-invasive methods including MR imaging and assay of several autoantibodies(e.g. aquaporin-4 autoantibodies)are recommended when each TDL is identified. The radiological findings on MRI are characterized by size >2 cm, mass effect, perilesional edema, T2 weighted hypointense rim, peripheral diffusion restriction, open ring enhancement, vascular enhancement, and central vein sign. When atypical clinical and radiological presentations are present in patients with TDL, diagnosis may necessitate brain biopsy due to exclude alternative pathology(e.g. primary central nervous system lymphoma). Because treatments and outcomes for patients with TDL are dependent on each disease etiology including MS, NMOSD, ADEM or others, we should always clarify the entire picture behind the disease.

Per-Vessel Level Analysis of Fractional Flow Reserve and Instantaneous Wave-Free Ratio Discordance　- Insights From the AJIP Registry.

BACKGROUND: The per-vessel level impact of physiological pattern of disease on the discordance between fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) has not been clarified.Methods and Results:Using the AJIP registry, vessels with FFR/iFR discordance (133/671 [19.8%]) were analyzed. In the left anterior descending artery (LAD), physiologically diffuse disease, as assessed by pressure-wire pullback, was associated with FFR-/iFR+ (83.3% [40/48]), while physiologically focal disease was associated with FFR+/iFR- (57.4% [31/54]), significantly (P<0.0001). These differences were not significant in non-LAD (P=0.17). CONCLUSIONS: The impact of physiological pattern of disease on FFR/iFR discordance is more pronounced in the LAD.

Prevalence of gout and asymptomatic hyperuricemia in the pediatric population: a cross-sectional study of a Japanese health insurance database.

BACKGROUND: Although gout is rare in children, chronic sustained hyperuricemia can lead to monosodium urate deposits progressing to gout, just as in adults. This study assessed prevalence and characteristics of gout and asymptomatic hyperuricemia, and incidence of gouty arthritis in the pediatric population, using data from Japanese health insurance claims. The diagnosis and treatment of pediatric gout and hyperuricemia were analyzed, and specific characteristics of those patients were assessed. Since Japanese guidelines recommend treatment with uric acid lowering drugs for asymptomatic hyperuricemia as well as for gout, these data were also used to investigate the real-world use of uric acid lowering drugs in a pediatric population. METHODS: This cross-sectional study was based on a 2016-2017 Japanese health insurance claims database, one of the largest epidemiology claims databases available in Japan, which included 356,790 males and 339,487 females 0-18 years of age. Outcomes were measured for prevalence, patient characteristics, treatment with uric acid lowering drugs for gout and asymptomatic hyperuricemia, and prevalence and incidence of gouty arthritis. Because uric acid can be elevated by some forms of chemotherapy, data from patients under treatment for malignancies were excluded from consideration. RESULTS: Total prevalence of gout and asymptomatic hyperuricemia in 0-18 year-olds was 0.040% (276/696,277 patients), with gout prevalence at 0.007% (48/696,277) and asymptomatic hyperuricemia at 0.033% (228/696,277). Prevalence of gout and asymptomatic hyperuricemia was highest in adolescent males, at 0.135% (176/130,823). The most common comorbidities for gout and asymptomatic hyperuricemia were metabolic syndrome at 42.8% (118/276) and kidney disease at 34.8% (96/276). Of the patients diagnosed with gout or asymptomatic hyperuricemia, 35.1% (97/276) were treated with uric acid lowering drugs. Gouty arthritis developed in 43.8% (21/48) of gout patients during the study, at an incidence of 0.65 flares/person-year. CONCLUSIONS: Even the pediatric population could be affected by asymptomatic hyperuricemia, gout, and gouty arthritis, and uric acid lowering drugs are being used in this population even though those drugs have not been approved for pediatric indications. Such off-label use may indicate a potential need for therapeutic agents in this population. TRIAL REGISTRATION: UMIN000036029 .