Salivary gland ultrasonography findings are associated with clinical, histological, and serologic features of Sjögren's syndrome.

OBJECTIVE: Salivary gland ultrasonography (SGUS) has been applied in the diagnosis of Sjögren's syndrome (SS). The aim of this study is to investigate the association of SGUS findings with clinical, histological, and serologic features of SS. METHODS: A total of 104 patients with suspected SS underwent SGUS for evaluation of salivary gland involvement. Patients with primary SS were determined according to the classification criteria for SS. The parenchymal inhomogeneity of bilateral parotid and submandibular glands was graded from 0 (homogeneity) to 4 (gross inhomogeneity). Receiver operating characteristic curve analysis was performed to compare the diagnostic performance of different SGUS scoring methods. Clinical and serologic features were compared between groups classified by SGUS score. The association between SGUS and these features of SS was explored by multivariable linear regression analysis. RESULTS: Study participants were predominantly women (96.2%) and had a mean age of 54.1 years. Eighty-seven patients and 88 patients with primary SS were identified based on AECG criteria and ACR/EULAR classification criteria for SS, respectively. Among the different scoring methods, the sum of the grades of four salivary glands (range 0-16) had the best diagnostic performance, with sensitivity of 77.3% and specificity of 87.5% (cutoff value, 7) for distinguishing primary SS from sicca non-SS. SGUS score was associated with focus score in labial salivary gland biopsy (ß = 0.240, p = 0.033) and anti-Ro/SSA serology (ß = 0.283, p = 0.016) and inversely associated with unstimulated whole salivary flow (ß = -0.298, p = 0.011). CONCLUSION: Ultrasonography of major salivary glands is associated with histopathology of minor salivary glands, serology of SS, and salivary gland function.

Effect of alcohol consumption and smoking on disease damage in systemic lupus erythematosus: data from the Korean Lupus Network (KORNET) registry.

Background We assessed correlations of smoking habits and alcohol consumption with disease activity or damage in patients with systemic lupus erythematosus (SLE). Methods A total of 505 patients with SLE were enrolled in the Korean Lupus Network (KORNET) SLE registry from January 2014 to January 2016. Disease activity and organ damage were measured by the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index, respectively. Multivariate logistic regression analysis was used to analyze associations with cutaneous lesions. Results There were no differences in SLEDAI-2K and SLICC/ACR damage indices according to either smoking status or alcohol consumption. More frequent cutaneous damage was observed in current alcohol drinkers compared with non-current alcohol drinkers ( p = 0.020). Cutaneous damage was significantly associated with alcohol consumption (odds ratio (OR) 4.048, 95% confidence interval (CI) 1.251-12.102, p = 0.020). Both low (1-5 glasses/week) and high (≥6 glasses/week) amounts of alcohol consumption had a significant impact on cutaneous damage compared with the absence of current alcohol consumption ( p = 0.033 and p = 0.027, respectively). Pairwise comparison of alcohol consumption and smoking status with cutaneous damage showed that only alcohol consumption was significantly associated with the presence of cutaneous damage, compared with non-current alcohol consumption and non-current smoking (OR 3.513, 95% CI 1.130-10.920, p =0.030). Conclusions Current alcohol consumption, but not smoking, might influence the development of cutaneous damage in patients with SLE.

Pain, xerostomia, and younger age are major determinants of fatigue in Korean patients with primary Sjögren's syndrome: a cohort study.

OBJECTIVES: Fatigue is a common clinical manifestation in patients with primary Sjögren's syndrome (pSS). The aims of this study were to investigate the association between fatigue severity and other clinical characteristics in pSS patients and to determine the factors contributing to fatigue. METHOD: We analysed 257 participants from the Korean Initiative of pSS (KISS), a prospective pSS cohort. Fatigue was assessed according to the fatigue domain of the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient-Reported Index (ESSPRI). Health-related quality of life (HRQoL) was evaluated using the EuroQol-5 dimensions (EQ-5D) questionnaire. Multiple linear regression analysis was used to estimate the effect of each variable on fatigue severity. RESULTS: The median total ESSPRI score was 5 [interquartile range (IQR) 4-6]. Thirty-four per cent of patients reported a fatigue score > 5. Younger and premenopausal patients presented with more fatigue (p = 0.013 and p < 0.001, respectively). Higher Xerostomia Inventory (XI) scale (p < 0.001) and Ocular Surface Dryness Index (OSDI) (p < 0.001) scores were observed in patients with a fatigue score > 5. Pain, xerostomia, and age were determined to be significantly associated with fatigue severity after adjusting for depression/anxiety, OSDI score, and the presence of fibromyalgia using a multivariate general linear model. The ESSPRI fatigue score was correlated with the EQ-5D by time trade-off (TTO) values and visual analogue scale (VAS) scores. CONCLUSIONS: In Korean patients with pSS, younger age, xerostomia, and pain were correlated significantly with fatigue, and fatigue was associated with HRQoL.

Urine ß2-microglobulin is associated with clinical disease activity and renal involvement in female patients with systemic lupus erythematosus.

OBJECTIVE: We investigated the association of serum and urine ß2-microglobulin (ß2MG) with renal involvement and clinical disease activity in systemic lupus erythematosus (SLE). METHODS: Sixty-four female patients with SLE were enrolled. We assessed SLE disease activity (SLEDAI)-2K and measured serum and urine ß2MG levels, as well as complement (C3 and C4) and anti-dsDNA levels. According to the SLEDAI scores, two groups were categorized: low (0-5 of SLEDAI) and high (6-19 of SLEDAI) disease activity groups. The presence of renal involvement was determined by renal SLEDAI score. Statistical analysis was performed using Spearman's correlation analysis, Mann-Whitney U test, multivariate regression analysis, and logistic regression analysis. RESULTS: Urine ß2MG levels were significantly different between low and high SLEDAI groups (p = 0.001), but not for serum ß2MG levels (p = 0.579). Patients with renal involvement showed higher urine ß2MG levels compared to those without renal involvement (p < 0.001), but again there was not a difference in serum ß2MG levels (p = 0.228). Urine ß2MG was closely associated with SLEDAI (r = 0.363, p = 0.003), renal SLEDAI (r = 0.479, p < 0.001), urine protein/Cr (r = 0.416, p = 0.001), and ESR (r = 0.347, p = 0.006), but not serum ß2MG (r = 0.245, p = 0.051). Urine ß2MG level was identified as a surrogate for renal involvement (p = 0.009, OR = 1.017, 95% CI 1.004-1.030) and overall disease activity (p = 0.009, OR = 1.020, 95% CI 1.005-1.036). CONCLUSIONS: We demonstrated that urine ß2MG levels are associated with renal involvement and overall clinical disease activity in SLE.

Arterial stiffness and proinflammatory cytokines in fibromyalgia syndrome.

OBJECTIVES: We assessed arterial stiffness and inflammatory cytokine profiles in fibromyalgia syndrome (FMS) patients and analysed the association between them. METHODS: Twenty-seven FMS patients and 29 age-matched premenopausal healthy controls were enrolled in this study. Arterial stiffness was assessed by pulse wave velocity (PWV) and augmentation index (AIx) from pulse waveform analysis. Levels of serum interleukin-1ß (IL-1ß), IL-6, IL-8, and vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assay, and a colorimetric assay was used for measurement of serum nitric oxide (NO) metabolites (nitrate and nitrite, NOx) level. Statistical analyses included the Mann-Whitney U-test and Spearman's correlation coefficient analysis. RESULTS: Higher AIx and AIx@HR75 (aortic AIx at a heart rate of 75 beats/min) were noted in FMS compared to those in the controls after adjustment using covariants (p(adj)=0.023 and p(adj)<0.001). However, there were no differences between the three regional PWVs of the two groups at the aorta-femoral, femoral-dorsalis, and aorta-radialis arteries (p(adj)>0.05 for all). FMS subjects had significantly higher serum IL-8 levels than did the healthy controls (327.9±588.7 vs. 76.4±90.5, p(adj)=0.041). However, there were no significant differences in serum IL-1ß, IL-6, VEGF, or NOx levels between the FMS patients and the controls (p(adj)>0.05 of all). Serum IL-8 level did not correlate with PWV and AIx in FMS patients. CONCLUSIONS: This study demonstrates higher AIx and IL-8 levels in FMS subjects compared to those of the controls. However, arterial stiffness including AIx in FMS was not determined by the serum IL-8 level.

The Severe Cognitive Impairment Rating Scale--an instrument for the assessment of cognition in moderate to severe dementia patients.

BACKGROUND/AIMS: This study aimed to develop a brief, reliable and valid test for cognitive function of severely demented patients. METHODS: We constructed the Severe Cognitive Impairment Rating Scale, which consisted of 11 items covering memory, language, visuospatial function, frontal function and orientation, and investigated its reliability and validity on 267 subjects [normal: 65, very mild Alzheimer's disease (AD): 42, mild AD: 58, moderate AD: 36, severe AD: 44, profound AD: 22]. RESULTS: The internal consistency obtained by Cronbach's coefficient alpha was 0.93. The interrater reliability and test-retest reliability in the moderately to severely impaired subjects with an MMSE score of

A normative study of the Revised Hasegawa Dementia Scale: comparison of demographic influences between the Revised Hasegawa Dementia Scale and the Mini-Mental Status Examination.

BACKGROUND/AIMS: We investigated the demographic influence on the performance of the Revised Hasegawa Dementia Scale (HDS-R) and provided normative data of the HDS-R in the elderly. METHODS: The HDS-R was administered to 803 community-dwelling cognitively normal elderly subjects aged 55 years or over. Cognitive disorders and psychiatric disorders were strictly excluded using the CERAD-K assessment packet and the Mini-International Neuropsychiatric Interview. The demographic influence on the performance of the HDS-R was examined using multiple linear regression analyses, and compared with that on the performance of the Mini-Mental Status Examination (MMSE) using the Chow test and t statistics. Overlapping strata were used in developing age-, education- and gender-specific normative data of the HDS-R. RESULTS: Age, education, and gender influenced significantly the performance of the HDS-R, and explained 22.5% of the total score variance. Older age, lower education, and male gender were associated with lower performance of the HDS-R. However, the demographic influence on the HDS-R was much weaker than that on the MMSE (t = 5.578, d.f. = 800, p < 0.001). The normative data of the HDS-R stratified by age (60-69, 70-79, > or =80), education (0-6, 7-12, > or =13), and gender were presented. CONCLUSIONS: The HDS-R was more robust to demographic influences than the MMSE, and normative data may contribute to improving further its diagnostic accuracy for dementia.

Depression in vascular dementia is quantitatively and qualitatively different from depression in Alzheimer's disease.

BACKGROUND/AIMS: To compare the prevalence and characteristics of depression in vascular dementia (VaD) and Alzheimer's disease (AD) after adjusting for dementia severity and gender. METHODS: One hundred and eight pairs of VaD and AD patients matched for dementia severity and gender were assessed. RESULTS: Major depressive disorder (MDD) was more prevalent in the VaD group than in the AD group (20.4% in VaD, 10.2% in AD, p = 0.04, Cochran-Mantel-Haenszel, CMH, test) regardless of the dementia severity and gender. The odds ratio for developing MDD in the VaD group versus the AD group was estimated to be 2.20 (95% confidence interval = 1.02-4.74). Neurovegetative symptoms such as 'felt tired and weak all the time' (30.6% in VaD, 13.9% in AD, p = 0.003, CMH test) and 'changed weight without trying' (16.7% in VaD, 6.5% in AD, p = 0.02, CMH test) were more prevalent in the VaD group than in the AD group. CONCLUSION: Depression in VaD was quantitatively and qualitatively different from that in AD regardless of the severity of dementia and gender; depression was more prevalent, severer and more retarded and vegetative in VaD than in AD.

Association between the HLA-DRB1 gene and clinical features of systemic sclerosis in Korea.

OBJECTIVE: To determine whether HLA-DR alleles are associated with the development and clinical features of systemic sclerosis (SSc) in Koreans. METHODS: Seventy-nine patients (74 women and five men; 45 diffuse types and 34 limited types; mean age at diagnosis 43.9 years) fulfilling the American College of Rheumatology (ACR) classification criteria for SSc were enrolled. The controls were 144 healthy, disease-free Koreans. HLA-DRB1 genotypes were assessed by the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. RESULTS: The HLA-DRB1*15 allele was increased in anti-topoisomerase I autoantibody (anti-topo I)-positive SSc patients [p = 0.003, p corrected (p(corr)) = 0.039, odds ratio (OR) = 3.43, 95% confidence interval (CI) 1.45-8.13] compared with controls. The DRB1*11 allele was also observed more frequently in anti-topo I-positive SSc than in controls (13.3% vs. 4.2%) but not statistically significant (p = 0.053, p(corr) = 0.689). In patients with SSc, the DRB1*04 allele was associated with subcutaneous calcinosis (p = 0.048, OR = 4.56, 95% CI 1.07-19.37). Patients with overlap syndrome showed a negative association with the DRB1*04 allele (p = 0.036, OR = 0.26, 95% CI 0.08-0.91). CONCLUSION: The HLA-DRB1*15 allele was associated with the development of anti-topo I-positive SSc in Koreans. In addition, the DRB1*04 allele was associated with certain clinical features in SSc patients.

Cervical spine involvement in longstanding ankylosing spondylitis.

OBJECTIVE: To investigate the degree of ossification and the frequency of ankylosis between the atlas and the dens of the axis in patients with longstanding ankylosing spondylitis (AS), to assess radiological involvement of the cervical spine, and to determine their correlations with structural severity and clinical variables, including neurological abnormalities. METHODS: In 61 AS patients with disease duration over 7 years, the findings of conventional radiographs were graded by the Bath Ankylosing Spondylitis Radiology Index (BASRI), and the ossification levels between the atlas and the dens and the severity of zygapophyseal (ZA) joint lesions were scored using multislice CT. Neurological examinations and somatosensory evoked potentials (SSEP) were performed by neurologists. RESULTS: According to the BASRI, 50 patients (82.0%) had radiological changes of the cervical spine > or = score 1. Thirty-seven patients (60.6%) revealed a certain extent of the atlantodental ossification, and the presence of partial or complete atlantodental ankylosis was seen over 30% of the patients. The BASRI-cervical spine score and the atlantodental ossification levels correlated with disease duration. ZA involvement was observed in 49 patients (80.3%), including 23 with ZA fusion (37.7%). Although 4 of 11 patients with atlantoaxial subluxation showed abnormal SSEP none had significant neurological complications. This might be attributed in part to atlantodental ankylosis and ZA fusion. Finally, ossifications of the anterior and posterior longitudinal ligaments were found 26.2 and 29.5%, respectively. CONCLUSION: Cervical spine involvement and atlantodental ossification or ankylosis appear to be common in patients with longstanding AS, and to be particularly more severe in patients with a longer disease duration.

Validation of the classification criteria commonly used in Korea and a modified set of preliminary criteria for Behçet's disease: a multi-center study.

OBJECTIVE: Recently we have proposed a modified set of criteria to settle the questions raised regarding the International Study Group (ISG) criteria for Behçet's disease (BD). The aim of the present study was to validate the two pre-existing criteria sets commonly used in Korea, the ISG criteria and the criteria of the Behçet's Disease Research Committee of Japan (Japanese criteria), as well as the proposed modified criteria. METHODS: The study population included 155 consecutive patients with BD and 170 controls with non-Behçet's rheumatic diseases. Detailed data for all of the subjects were recorded prospectively by the participating physicians on a standard form that listed the clinical features of BD. The sensitivity, specificity, and accuracy of each set of the criteria were measured. RESULTS: Of the three criteria sets employed, the modified criteria were the most accurate, with an accuracy of 96.3%. The ISG criteria often failed to classify the following patients with BD: patients with only oral and genital ulcerations, certain patients with intestinal ulcerations, patients who did not manifest oral ulcerations, and patients with acute disease but fewer than three recurrent oral ulceration relapses in a 1-year period. The Japanese criteria also failed to categorize the following patients with BD: patients with oral and genital ulcerations, and patients with oral ulcerations, skin lesions, and a positive pathergy reaction. In addition, the Japanese criteria misclassified some of the control subjects with non-Behçet's uveitis as having BD. CONCLUSIONS: The results of this study suggest that there are some points that need to be reconsidered in the clinical application of the two pre-existing sets of criteria. Although the modified criteria were the most accurate, further validation studies will be required in other ethnic populations.

Association between HLA-DR B1 and clinical features of adult onset Still's disease in Korea.

OBJECTIVE: To determine whether HLA-DR alleles are associated with the development and clinical features of Adult Onset Still's Disease (AOSD) in Korea. METHODS: Forty-seven patients (41 women, 6 men, mean age at diagnosis 31.6 yr) meeting Yamaguchi's criteria for AOSD and 144 healthy controls were enrolled in this study. The patients with AOSD were subdivided into groups according to their chronicity: monocyclic systemic, polycyclic systemic, and chronic destructive type, and were furthermore classified as non-articular, oligoarticular or polyarticular types (having arthritis involving 5 or more joints) according to the extent of articular involvement. HLA-DRB1 genotypes were assessed by PCR-SSOP. RESULTS: Patients with AOSD had more frequent DRB1*12 (p = 0.028, relative risk (RR) = 2.27, 95% confidence interval (CI): 1.08-4.80) and DRB1*15 (p = 0.013, RR = 2.16, 95% CI: 1.17-4.00). They had less frequent DRB1*04 (p = 0.006, RR = 0.35, 95% CI: 0.16-0.75) compared to controls. DRB1*14 (p = 0.011, RR = 3.80, 95% CI: 1.27-11.31) were associated with the monocyclic systemic type. CONCLUSION: Korean AOSD patients had more frequent DRB1*12 and DRB1*15, and less frequent HLA-DRB1*04. The patients with the monocyclic systemic type had more frequent DRB1*14 alleles. This study suggests that Korean AOSD patients have distinct immunogenetic profiles, and that it would be valuable to assess the relationships between HLA-DRB1 genes and polymorphisms of proinflammatory cytokines in the pathogenesis of AOSD.

Recombinant mouse muscle adenylosuccinate synthetase: overexpression, kinetics, and crystal structure.

Vertebrates possess two isozymes of adenylosuccinate synthetase. The acidic isozyme is similar to the synthetase from bacteria and plants, being involved in the de novo biosynthesis of AMP, whereas the basic isozyme participates in the purine nucleotide cycle. Reported here is the first instance of overexpression and crystal structure determination of a basic isozyme of adenylosuccinate synthetase. The recombinant mouse muscle enzyme purified to homogeneity in milligram quantities exhibits a specific activity comparable with that of the rat muscle enzyme isolated from tissue and K(m) parameters for GTP, IMP, and l-aspartate (12, 45, and 140 microm, respectively) similar to those of the enzyme from Escherichia coli. The mouse muscle and E. coli enzymes have similar polypeptide folds, differing primarily in the conformation of loops, involved in substrate recognition and stabilization of the transition state. Residues 65-68 of the muscle isozyme adopt a conformation not observed in any previous synthetase structure. In its new conformation, segment 65-68 forms intramolecular hydrogen bonds with residues essential for the recognition of IMP and, in fact, sterically excludes IMP from the active site. Observed differences in ligand recognition among adenylosuccinate synthetases may be due in part to conformational variations in the IMP pocket of the ligand-free enzymes.

FcgammaRIIa/IIIa polymorphism and its association with clinical manifestations in Korean lupus patients.

The aim of this study was to determine the distribution of the FcgammaRlla and FcgammaRIIIa polymorphisms and their association with clinical manifestations in Korean lupus patients. Three hundred SLE (systemic lupus erythematosus) patients (48 male, 252 female) meeting 1982 ACR criteria and 197 Korean disease-free controls were enrolled. Genotyping for FcgammaRlla 131 R/H and FcgammaRIIIa 176 F/V was performed by PCR of genomic DNA using allele-specific primers and the FcgammaRIIIa genotype was confirmed by direct sequencing of PCR product in some cases. There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE and the controls (P=0.002 for R/R131 vs R/H131 and H/H131, OR 2.5 (95% Cl 1.4-4.5), but not in FcgammaRIIIa genotypes. FcgammaRIIa-R allele was a significant predictor of lupus nephritis, as compared with SLE patients without nephritis (P=0.034 for R131 vs H131, OR 1.4 (95% Cl 1.03-1.9)), but proliferative nephritis (WHO class III and IV) was less common in patients with FcgammaRlla-R/R131 and in FcgammaRIIa-R allele. In 300 SLE patients, high binding allele combination H131/V176 was less common in SLE with nephritis than in SLE without nephritis. Hemolytic anemia was less common in R131/F176 allele combination among four FcgammaRIIa/FcgammaRIIIa allelic combinations. Male SLE patients showed a higher frequency of renal involvement, serositis, thrombocytopenia, malar rash and discoid rash than female SLE, and male SLE had a higher frequency of FcgammaRIIa-R/R131 or R131-allele than male controls, but FcgammaRIIa or FcgammaRIIIa genotypes had no association with renal involvement in male SLE patients. FcgammaRIIa-H/H131 showed a higher frequency of hemolytic anemia and less pulmonary complications in male SLE. Female SLE patients showed higher frequency of any hematologic abnormality, lymphopenia, anticardiolipin antibody (+) and anti-Ro antibody (+) than male SLE, and had earlier onset of first symptoms. There was no skewing in FcgammaRIIa or FcgammaRIIIa genotypes between female SLE and female controls, but FcgammaRIIa-R131 allele showed skewing between female SLE with nephritis and female SLE without nephritis. The age at onset of thrombocytopenia was earlier in FcgammaRIIa R/R131 among three FcgammaRIIa genotypes, and serositis in FcgammaRIIIa-F/F176 among three FcgammaRIIIa genotypes. FcgammaRIIa-R131 homozygote was a major predisposing factor to the development of SLE and FcgammaRIIa-RI31 homozygote and R131 allele were a predisposing factor, and H131/V176 was a protective allele combination in lupus nephritis. In contrast to other ethnic patients, in our study cohort, clinical manifestation was different between male and female, and FcgammaRIIa and FcgammaRIIIa showed somewhat different clinical associations between the genders.

The demographics of pelvic floor disorders: current observations and future projections.

OBJECTIVE: Our aim was to assess current demand for care of pelvic floor disorders and create projections for future demand for care. We also sought to better understand the characteristics of women seeking care. STUDY DESIGN: Current demand for care was calculated by comparing those women seeking care through the female pelvic floor disorders clinic with those women of the same age range at risk within an integrated health care delivery program. Patients underwent complete urogynecologic evaluation including cystometry. Women seeking care were compared with regard to age, distribution of conditions (pelvic organ prolapse, stress conditions, urge conditions), and probability of undergoing surgery. Modeling the study population by use of data from the US Census Bureau, which projects population changes over the next 30 years, created predictions of future demand. RESULTS: Data were available on 2070 consecutive patients with an age range of 30 to 89 years normally distributed around a median age of 61.5 years drawn from an at-risk population of 149,000 women aged 30 to 89 years. Older women generated more consults per 1000 woman years than did the younger cohorts (1.7 vs 18.6 consults per 1000 woman years for those 30-39 years old vs those 70-79 years old; P <.05). Estimates of growth in demand at 30 years indicate a 45% increase in demand while net growth of the same population segment should be 22%. Stress conditions were more common among younger women and urge conditions were more common among older women. Pelvic organ prolapse was equally distributed throughout the age ranges. CONCLUSIONS: Over the next 30 years, growth in demand for services to care for female pelvic floor disorders will increase at twice the rate of growth of the same population. Demand for care for pelvic floor disorders comes from a wide age range of women, although mature age groups generate 10 times the number of consults per 1000 woman years as do their younger counterparts. Age plays a major role in the distribution of conditions with which patients present. These findings have broad implications for those responsible for administering programs to care for women, allocating research funds in women's health and geriatrics, and training physicians to meet this rapidly escalating demand.

Systemic lupus erythematosus presenting earlier as retinal vaso-occlusion.

Retinal vascular lesions are the most common ophthalmologic manifestation of systemic lupus erythematosus (SLE), occurring in 3% to 29% of cases, generally late in the disease. More rare is the severe vaso-occlusive disease, often termed "retinal vasculitis", which includes central retinal artery occlusion, multifocal arteriolar occlusions, extensive capillary nonperfusion and central venous occlusion. Patients with SLE and raised serum concentrations of anticardiolipin antibodies (ACA) have a higher risk of developing occlusive ocular vascular disease. We report a case in which retinal involvement was an earlier manifestation of SLE in a patient without ACA.