Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Relapse in patients with antineutrophil cytoplasmic antibody-associated vasculitis undergoing dialysis: a single-centre retrospective study in South Korea.

OBJECTIVES: The disease activity of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) can decrease after dialysis, and relapse after dialysis is not well-studied. We investigated the clinical manifestations and factors associated with relapse in patients with AAV undergoing dialysis. METHODS: This retrospective study included data of patients with AAV undergoing dialysis due to renal involvement from July 2005 to March 2021 in a single tertiary centre in Seoul, Korea. Cox regression analysis was performed to identify relapse-associated factors. RESULTS: The study cohort included 38 patients with a median age of 64.0 years; 28 (73.7%) were female, and 35 (92.1%) patients were diagnosed with microscopic polyangiitis (MPA). At diagnosis, the mean Birmingham vasculitis activity score (BVAS) was 18.3 and 66.3% of the patients exhibited pulmonary manifestations. During follow-up, 12 patients experienced AAV relapse, including nine patients with diffuse alveolar haemorrhage (DAH), two patients with aggravated interstitial lung disease, and one patient with DAH accompanied with neuropathy. Clinical features including age, sex, and baseline BVAS did not significantly differ between the relapse and non-relapse groups. By univariable analysis, lung infiltration, DAH, corticosteroid pulse therapy for induction, and mean corticosteroid dose were significantly associated with relapse. Multivariable analysis revealed that DAH (adjusted hazard ratio 5.509, 95% CI 1.569-19.339; P=0.008) and mean corticosteroid dose (adjusted hazard ratio 1.381, 95% CI 1.161-1.642; P<0.001) were significantly associated with relapse. CONCLUSIONS: In patients with AAV undergoing dialysis, DAH and mean corticosteroid dose were significantly associated with relapse, highlighting the importance of close monitoring.

Circulating and renal fibrocytes are associated with interstitial fibrosis in lupus nephritis.

OBJECTIVES: Fibrocytes, the extracellular matrix-producing cells derived from bone marrow progenitors, contribute to organ fibrosis. We investigated the presence and characteristics of fibrocytes in the peripheral blood and kidney of patients with lupus nephritis (LN), and the association of the abundance of fibrocytes with renal tubular epithelial cells (RTECs) in LN fibrogenesis. METHODS: Fibrocytes were identified with type I collagen (colI), α-smooth muscle actin (α-SMA), CD34 and CD45 using flow cytometry and confocal imaging. The associations between the levels of fibrocytes and pathological features of patients with LN were analysed. The contribution of RTECs to fibrocyte generation was determined using LN sera-treated HK-2 cells. RESULTS: Spindle-shaped fibrocytes (colI+α-SMA+CD34+CD45+ cells) were present in the peripheral blood and their abundance was especially high in LN patients with interstitial fibrosis compared with healthy control. Renal fibrocytes (colI+α-SMA+CD45+ cells) were found in the tubulointerstitium in patients with LN, and their numbers were significantly associated with the degrees of chronicity indices including interstitial fibrosis and renal dysfunction. Stimulation of peripheral blood mononuclear cells with supernatants from LN serum-treated HK-2 cells led to a significant generation of fibrocytes, which was abrogated by the addition of IL-6 neutralizing antibody. CONCLUSION: Fibrocytes were significantly increased in the blood and kidney tissue of patients with LN, especially those with interstitial fibrosis. Fibrocytes could be differentiated from blood cells, with an active contribution from RTECs. Our results show a possible link between fibrocytes and tubulointerstitial fibrosis, which may serve as a novel therapeutic target for LN fibrogenesis.

Incidence of and risk factors for myelodysplastic syndromes in patients with rheumatologic diseases.

OBJECTIVE: We investigated the incidence rate and risk factors of myelodysplastic syndromes (MDS) in patients with rheumatologic disease. METHODS: We conducted a retrospective cohort study of patients who were diagnosed with rheumatologic diseases at a tertiary-care hospital between May 2009 and July 2022 and identified the patients who were subsequently diagnosed with MDS. Each patient with MDS was matched with five age- and sex-matched controls chosen from the cohort of patients with each specific rheumatologic disease. RESULTS: During a total follow-up of 55 841 person-years (PY), MDS occurred in 64 patients, yielding an incidence rate of 1.15/1000 PY (median age, 57.0 [IQR, 41.0-69.0]; median duration to MDS diagnosis, 6.5 years [IQR, 3.0-9.0]). In an age-matched analysis, systemic lupus erythematosus (SLE) was a significant risk factor for MDS (adjusted hazard ratio, 2.61 [CI, 1.19-36.06], P= 0.01). Refractory cytopenia with multilineage dysplasia was the most common phenotype of MDS (35.9%), and more than half of the patients had karyotypes with favorable prognoses (54.7%). Compared with matched controls, rheumatoid arthritis, SLE, and ankylosing spondylitis patients with MDS had lower levels of haemoglobin at the time of diagnosis of rheumatologic disease. Furthermore, the MDS patients with SLE and Behcet's disease had higher levels of glucocorticoid use in terms of frequency of use or mean dose than the control patients. CONCLUSION: SLE is a significant risk factor for MDS among patients with rheumatologic diseases. A lower haemoglobin level at the time of diagnosis of rheumatologic disease was associated with the future development of MDS.

Aberrant cortico-striatal white matter connectivity and associated subregional microstructure of the striatum in obsessive-compulsive disorder.

The striatum and its cortical circuits play central roles in the pathophysiology of obsessive-compulsive disorder (OCD). The striatum is subdivided by cortical connections and functions; however, the anatomical aberrations in different cortico-striatal connections and coexisting microstructural anomalies in striatal subregions of OCD patients are poorly understood. Thus, we aimed to elucidate the aberrations in cortico-striatal white matter (WM) connectivity and the associated subregional microstructure of the striatum in patients with OCD. From diffusion tensor/kurtosis imaging of 107 unmedicated OCD patients and 110 matched healthy controls (HCs), we calculated the cortico-striatal WM connectivity and segmented the striatum using probabilistic tractography. For the segmented striatal subregions, we measured average diffusion kurtosis values, which represent microstructural complexity. Connectivity and mean kurtosis values in each cortical target and associated striatal subregions were compared between groups. We identified significantly reduced orbitofrontal WM connectivity with its associated striatal subregion in patients with OCD compared to that in HCs. However, OCD patients exhibited significantly increased caudal-motor and parietal connectivity with the associated striatal subregions. The mean kurtosis values of the striatal subregions connected to the caudal-motor and parietal cortex were significantly decreased in OCD patients. Our results highlighted contrasting patterns of striatal WM connections with the orbitofrontal and caudal-motor/parietal cortices, thus supporting the cortico-striatal circuitry imbalance model of OCD. We suggest that aberrations in WM connections and the microstructure of their downstream regions in the caudal-motor-/parietal-striatal circuits may underlie OCD pathophysiology and further provide potential neuromodulation targets for the treatment of OCD.

Unbalanced fronto-pallidal neurocircuit underlying set shifting in obsessive-compulsive disorder.

Maladaptive habitual behaviours of obsessive-compulsive disorder are characterized by cognitive inflexibility, which hypothetically arises from dysfunctions of a certain cortico-basal ganglia-thalamo-cortical circuit including the ventrolateral prefrontal region. Inside this neurocircuit, an imbalance between distinct striatal projections to basal ganglia output nuclei, either directly or indirectly via the external globus pallidus, is suggested to be relevant for impaired arbitration between facilitation and inhibition of cortically initiated activity. However, current evidence of individually altered cortico-striatal or thalamo-cortical connectivities is insufficient to understand how cortical dysconnections are linked to the imbalanced basal ganglia system in patients. In this study, we aimed to identify aberrant ventrolateral prefronto-basal ganglia-thalamic subnetworks representing direct-indirect imbalance and its association with cognitive inflexibility in patients. To increase network detection sensitivity, we constructed a cortico-basal ganglia-thalamo-cortical network model incorporating striatal, pallidal and thalamic subregions defined by unsupervised clustering in 105 medication-free patients with obsessive-compulsive disorder (age = 25.05 ± 6.55 years, male/female = 70/35) and 99 healthy controls (age = 23.93 ± 5.80 years, male/female = 64/35). By using the network-based statistic method, we analysed group differences in subnetworks formed by suprathreshold dysconnectivities. Using linear regression models, we tested subnetwork dysconnectivity effects on symptom severity and set-shifting performance assessed by well-validated clinical and cognitive tests. Compared with the healthy controls, patients were slower to track the Part B sequence of the Trail Making Test when the effects of psychomotor and visuospatial functions were adjusted (t = 3.89, P < 0.001) and made more extradimensional shift errors (t = 4.09, P < 0.001). In addition to reduced fronto-striatal and striato-external pallidal connectivities and hypoconnected striato-thalamic subnetwork [P = 0.001, family-wise error rate (FWER) corrected], patients had hyperconnected fronto-external pallidal (P = 0.012, FWER corrected) and intra-thalamic (P = 0.015, FWER corrected) subnetworks compared with the healthy controls. Among the patients, the fronto-pallidal subnetwork alteration, especially ventrolateral prefronto-external globus pallidal hyperconnectivity, was associated with relatively fewer extradimensional shifting errors (ß = -0.30, P = 0.001). Our findings suggest that the hyperconnected fronto-external pallidal subnetwork may have an opposite effect to the imbalance caused by the reduced indirect pathway (fronto-striato-external pallidal) connectivities in patients. This ventrolateral prefrontal hyperconnectivity may help the external globus pallidus disinhibit basal ganglia output nuclei, which results in behavioural inhibition, so as to compensate for the impaired set shifting. We suggest the ventrolateral prefrontal and external globus pallidus as neuromodulatory targets for inflexible habitual behaviours in obsessive-compulsive disorder.

Prognostic value of proteinuria monitoring in anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To determine the prognostic significance of proteinuria monitoring in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We retrospectively analyzed the data of kidney biopsy-confirmed patients with AAV. Proteinuria was evaluated by a urine dipstick test. Poor renal outcome was defined as stage 4/5 chronic kidney disease (CKD) (estimated glomerular filtration rate < 30 mL/min/1.73 m2). RESULTS: We enrolled 77 patients with a median follow-up duration of 36 months (interquartile range, 18-79) in this study. Excluding 8 patients on dialysis at 6 months, 59/69 (85.5%) achieved remission after induction therapy. Patients were then divided into two groups according to the presence of proteinuria at 6 months after induction therapy (n = 29 with proteinuria, 40 without proteinuria). There was no significant difference in the rate of relapse or death according to the presence of proteinuria (p = 0.304 relapse, 0.401 death). In contrast, patients with proteinuria had significantly lower kidney function than those without proteinuria (41 vs. 53.5 mL/min/1.73 m2, p = 0.003). Multivariate analysis revealed that eGFR values at 6 months (hazard ratio [HR] 0.925; 95% CI 0.875-0.978, p = 0.006) and proteinuria at 6 months (HR 4.613; 95% CI 1.230-17.298, p = 0.023) were significantly associated with stage 4/5 CKD. CONCLUSION: The presence of proteinuria at 6 months after induction therapy and low renal function was significantly associated with a higher risk of stage 4/5 CKD in patients with AAV. Monitoring for proteinuria after induction therapy may help predict poor renal outcomes in patients with AAV.

Clinical features of systemic lupus erythematosus patients with splenomegaly: focussed on the cytopenias.

This study aimed to investigate the clinical features of splenomegaly, mainly focussing on cytopenia, in patients with systemic lupus erythematosus (SLE). Cytopenia was commonly observed in 111 SLE patients with splenomegaly (n = 79, 71.2%). During the follow-up period, two patients developed haematologic malignancy after the diagnosis of SLE and splenomegaly, but no patients experienced severe complications (e.g. splenic rupture) related to splenomegaly.

When MRI would be useful in patients without evidence of sacroiliitis on radiographs?

We aimed to identify when magnetic resonance imaging (MRI) would be useful to diagnose patients with suspected axial spondyloarthropathy (AxSpA) without evidence of sacroiliitis on radiographs. We retrospectively reviewed electronic medical records of patients who underwent pelvis MRI after radiographs at the rheumatology clinic in a single tertiary center in Korea. Patients underwent imaging from January 2020 to July 2022. We collected data including complete blood count, erythrocyte sedimentation rate, C-reactive protein (CRP), human leukocyte antigen (HLA)-B27, history of acute anterior uveitis (AAU), peripheral arthritis, dactylitis, inflammatory bowel disease (IBD), enthesopathy, and psoriasis. A total of 105 patients who showed no evidence of sacroiliitis on radiographs were included. The median age of patients was 41.0 years, and 44.8% were male. Of them, 34 showed sacroiliitis on MRI (group 1), and 71 showed no evidence of sacroiliitis even on MRI (group 2). Known AxSpA-related clinical features including AAU, peripheral arthritis, dactylitis, IBD, enthesopathy, and psoriasis were not different between the two groups. HLA-B27 positivity (79.4% vs. 40.0%, p < 0.001), median white blood cell count (7700 vs. 6300, p = 0.007), mean platelet count (307.7 ± 69.7 vs. 265.3 ± 68.9 × 103/µL, p = 0.005), and median CRP level (0.38 vs. 0.10, p = 0.001) showed significant differences between the two groups. In a multivariate analysis, HLA-B27 positivity and platelet count were significantly associated with sacroiliitis on MRI. In our cohort, sacroiliitis was observed on MRI in one-third of patients without radiographic evidence. MRI could be recommended to evaluate sacroiliitis in patients with positive HLA-B27 and a high platelet count.

Multiple toll-like receptors (TLRs) display differential bacterial and ligand specificity in the earthworm, Eisenia andrei.

Toll-like receptors (TLRs), an ancient and well-conserved group of pattern recognition receptors (PRRs), recognize conserved pathogen-associated molecular patterns. TLRs consist of three domains: the extracellular N-terminal domain, containing one or more leucine-rich repeats (LRRs), responsible for the recognizing and binding of antigens; the type-I transmembrane domain; and the intracellular domain known as the Toll/Interleukin-1 receptor (TIR) domain required for the downstream signaling pathway. We identified six new full-length complementary DNA (cDNA) sequences, Ean-TLR1/2/3/4/5/6. The deduced amino acid sequences indicate that Ean-TLRs consist of one signal peptide, one LRR N-terminal domain (Ean-TLR4/5), varying numbers of LRRs, one (Ean-TLR1/2/3/4/5) or two (Ean-TLR6) LRR C-terminal domains, one type-I transmembrane domain, and a TIR domain. In addition, a TIR domain alignment revealed that three conserved motifs, designated as Box 1, Box 2, and Box 3, contain essential amino acid residues for downstream signaling activity. Phylogenetic analysis of earthworm TLRs generated two separate evolutionary branches representing single (sccTLR) and multiple (mccTLR) cysteine cluster TLRs. Ean-TLR1/2/3/4 (sccTLR type) and Ean-TLR6 (mccTLR type) were clustered with corresponding types of previously reported earthworm TLRs as well as TLRs from Clitellata and Polychaete. As PRRs, earthworm TLRs should be capable of sensing a diverse range of pathogens. Except for Ean-TLR3, which was not responsive to any bacteria, earthworm TLR expression was significantly induced by Gram-positive but not Gram-negative bacteria. Moreover, it is likely that earthworms can differentiate between different species of Gram-positive bacteria via their TLR responses. The ligand specificity of earthworm TLRs suggests that their pathogenic ligand recognition is likely to be as specific and diverse as the mammalian TLR pathogen-sensing system.

Anti-S1/RBD-Specific Antibody Formation After SARS-CoV-2 Vaccination in Elderly Rheumatoid Arthritis Patients: Single-Center Prospective Observational Study.

BACKGROUND: The guidelines of coronavirus disease 2019 (COVID-19) vaccination in patients with rheumatoid arthritis (RA) have been continuously updated, with extensive discussion on the effectiveness of the COVID-19 booster vaccines and antibody generation associated with the different types of vaccine. We investigated the effects of the third dose of the mRNA vaccine on antibody titer and the factors associated with antibody production in patients with RA who had previously received two doses of the ChAdOx1-S nCoV-19 vaccine. METHODS: Between October 14, 2021 and June 17, 2022, two patient groups diagnosed with RA were recruited prospectively: one with two doses of ChAdOx1-S nCoV-19 and the second group with the additional third mRNA vaccine. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody titers were determined through semiquantitative anti-SARS-CoV-2 spike (S) electrochemiluminescence immunoassay. Antibody titers were compared in both groups considering clinical features and medications. Multivariate logistic regression was performed to identify the factors associated with antibody production. Also, we followed up the antibody titers of whom completed the 3rd mRNA vaccination. RESULTS: Among 261 patients, all patients were over 60 years old except for 7 patients and the average age was 65 years; 153 had completed two doses of ChAdOx1-S nCoV-19, while 108 patients had also received the third mRNA vaccine. The positive rates of anti-SARS-CoV-2 anti-S1/receptor binding domain-specific antibody (titer > 0.8 U/mL) were 97% (149/153) and 99% (107/108) respectively. However, positive rates for high antibody titer (> 250 U/mL) were found in only 31% (47/153) of group 1 but 94% (102/108) of group 2. Multivariate analysis revealed that corticosteroid use (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.16-0.75), older age (OR, 0.91; 95% CI, 0.860-0.98), and male sex (OR, 0.23; 95% CI, 0.07-0.74) were associated with a lower rate of high antibody titer acquisition after two doses of ChAdOx1-S nCoV-19. Waning of antibody titers was observed in only two of 46 patients who followed up twice after the third mRNA vaccine inoculation. CONCLUSION: Our findings suggest that the third dose of the mRNA vaccine could be beneficial in RA patients with risk factors including older age, male sex, and corticosteroid use after two doses of ChAdOx1-S nCoV-19.

Functional Characterization of Allelic Variations of Human Cytochrome P450 2C8 (V181I, I244V, I331T, and L361F).

The human cytochrome P450 2C8 is responsible for the metabolism of various clinical drugs as well as endogenous fatty acids. Allelic variations can significantly influence the metabolic outcomes. In this study, we characterize the functional effects of four nonsynonymous single nucleotide polymorphisms *15, *16, *17, and *18 alleles recently identified in cytochrome P450 2C8. The recombinant allelic variant enzymes V181I, I244V, I331T, and L361F were successfully expressed in Escherichia coli and purified. The steady-state kinetic analysis of paclitaxel 6-hydroxylation revealed a significant reduction in the catalytic activities of the V181I, I244V, and L361F variants. The calculated catalytic efficiency (kcat/Km) of these variants was 5-26% of that of the wild-type enzyme. The reduced activities were due to both decreased kcat values and increased Km values of the variants. The epoxidation of arachidonic acid by the variants was analyzed. The L361F variant only exhibited 4-6% of the wild-type catalytic efficiency in ω-9- and ω-6-epoxidation reactions to produce 11,12-epoxyeicosatrienoic acid (EET) and 14,15-EET, respectively. These reductions were mainly due to a decrease in the kcat value of the L361F variant. The binding titration analysis of paclitaxel and arachidonic acid showed that all variants had similar affinities to those of the wild-type (10-14 µM for paclitaxel and 20-49 µM for arachidonic acid). The constructed paclitaxel docking model of the variant enzyme suggests that the L361F substitution leads to the incorrect orientation of paclitaxel in the active site, with the 6'C of paclitaxel displaced from the productive catalytic location. This study suggests that individuals carrying the newly identified P450 2C8 allelic variations are likely to have an altered metabolism of clinical medicines and production of fatty acid-derived signal molecules.

Caspase-6-cleaved tau is relevant in Alzheimer's disease and marginal in four-repeat tauopathies: Diagnostic and therapeutic implications.

AIM: Tau truncation (tr-tau) by active caspase-6 (aCasp-6) generates tau fragments that may be toxic. Yet the relationship between aCasp-6, different forms of tr-tau and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer's disease (AD) and other tauopathies remains unclear. METHODS: We generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used five-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau and their co-occurrence in healthy controls, AD and primary tauopathies. RESULTS: Casp-6 activation was strongest in AD and Pick's disease (PiD) but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD and PiD lacked p-tau aggregates, a finding we confirmed using several p-tau antibodies. CONCLUSIONS: Early modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p-tau antibodies. Therapeutic strategies against tr-tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD and PiD supports the development of biofluid biomarkers against tr-tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level.

Renal outcomes of transient proteinuria in patients with systemic lupus erythematosus treated with corticosteroid therapy alone.

OBJECTIVES: To examine the long-term renal outcomes of systemic lupus erythematosus (SLE) patients with transient proteinuria. METHODS: The medical records of SLE patients who showed improvement in proteinuria (urine protein/creatinine ratio < 500 mg/g) after receiving corticosteroid therapy without immunosuppressants were reviewed. RESULTS: A total of 38 patients (mean creatinine: 0.74 ± 0.33 mg/dl) showed an improvement of proteinuria (1361 ± 1053 mg/g to 289 ± 125 mg/g) after receiving corticosteroid therapy alone for a median of 25 days (IQR, 10-55). After follow-up (median, 23 months [IQR, 15-121]), 25 (65%) patients maintained the resolution of proteinuria without renal dysfunction. The remaining 13 (34%) patients experienced a relapse of proteinuria during a median follow-up of 13.9 months from baseline (IQR, 1.6-25). There was no significant difference in the baseline laboratory data according to the occurrence of proteinuria relapse, but longer SLE disease duration at baseline was associated with the risk of proteinuria relapse (HR, 1.007; p = 0.033). Of the patients who underwent renal biopsy with proteinuria relapse, class II (53%) lupus nephritis was the most common pathology. None progressed to end-stage renal disease during an additional long-term further follow-up of median 33 months (IQR, 22-49) after proteinuria relapse. CONCLUSION: Two-thirds of SLE patients who showed improvement in proteinuria after corticosteroid alone maintained the non-proteinuric state without renal dysfunction. Thus, performing a kidney biopsy at the first onset of proteinuria could be delayed in patients who show an improvement in proteinuria after treatment with corticosteroids.

Angiographic patterns and temporal changes of arterial lesions in Behcet's disease.

BACKGROUND: Behcet's disease (BD) can entail vascular involvement in various forms including aneurysm. We evaluated the angiographic patterns and changes in arterial lesions over time in BD patients with arterial involvement. METHODS: We reviewed the medical records of BD patients diagnosed with arterial lesions between 1995 and 2018. Angiographic patterns were categorized as stenosis, occlusion, dilatation, or aneurysm. Patients were divided according to symptom duration (<5, 5-10, >10 years). Cox proportional-hazards model was used to evaluate the risk factors for vascular progression. RESULTS: 47 BD patients had arterial involvement in the following patterns: aneurysm (n = 31), stenosis (n = 17), dilatation (n = 13), and occlusion (n = 8). Aneurysm (70.8%) was the most common pattern in 24 patients with short (<5 years) symptom duration. Stenosis was more common (50.0%) in 12 patients with longer symptom durations (>10 years). In 23 patients with follow-up imaging (median, 5.7 years), eight (34.8%) developed 11 new lesions: stenosis (n = 5), dilatation (n = 1), and aneurysm (n = 5). One stenotic lesion progressed to occlusion, and two dilated lesions progressed to aneurysms. Lower extremity involvement and methotrexate use were associated with arterial progression, with hazard ratios of 5.716 (p = 0.029) and 0.101 (p = 0.049), respectively. CONCLUSION: In BD patients with arterial involvement, aneurysm was the most common pattern in earlier stages of BD, while stenosis was more common in later stages of BD. Methotrexate use was associated with lower risk of arterial lesion progression.

Predictive Factors for Rheumatoid Arthritis Flare After Switching From Intravenous to Subcutaneous Formulation of Tocilizumab in Real-World Practice.

BACKGROUND: To evaluate the incidence and related factors of rheumatoid arthritis (RA) flares after switching from intravenous tocilizumab (TCZ-IV) to subcutaneous tocilizumab (TCZ-SC) injection in stable RA patients. METHODS: We retrospectively evaluated the medical records of stable RA patients who used TCZ-IV for more than 6 months and switched to TCZ-SC between January 2013 and April 2020. RA flare was defined as an increase of more than 1.2 in the RA disease activity as assessed by the disease activity score in 28 joints. The factors associated with RA flare were evaluated by logistic regression analysis. RESULTS: Among 106 patients treated with TCZ-IV for > 6 months, 37 patients were switched to TCZ-SC after the acquisition of remission or low disease activity. RA flares occurred in 11 (29.7%) of patients who switched TCZ-SC. Results from the multivariable logistic analysis revealed that the dose of TCZ-IV per weight at switching (odds ratio [OR], 20.70; 95% confidence interval [CI], 2.22-192.84; P = 0.008) and methotrexate (MTX) non-use (OR, 8.53; 95% CI, 1.21-60.40; P = 0.032) were associated with the risk of RA flares after switching to TCZ-SC. Interestingly, most patients who switched back to TCZ-IV had their RA activity controlled again. CONCLUSION: MTX non-use and high dose of TCZ-IV per weight were associated with a risk of RA flare after switching to TCZ-SC. RA patients with these factors need to be carefully observed for flare after switching from TCZ-IV to TCZ-SC.

Comparative efficacy of low-dose versus regular-dose colchicine to prevent flares in gout patients initiated on urate-lowering therapies.

OBJECTIVE: The objective of this study was to compare the prophylactic effect of regular-dose (RD, 1.2 mg/day) vs low-dose (LD, 0.6 mg/day) colchicine on gout flare when initiating urate-lowering therapy. METHODS: In this retrospective cohort study, we included gout patients who were initiated on either allopurinol or febuxostat, in combination with colchicine therapy and followed them up for 3 months. We analysed the rates of gout flare and adverse events according to the dose of colchicine. We performed the inverse probability of treatment weighting (IPTW) and weighted logistic regression analysis to assess the treatment effect. Analysis of gout flares and adverse events was performed on an intention-to-treat (ITT) and per-protocol (PP) basis. RESULTS: Of the total of 419 patients with gout, 177 patients (42.2%) received LD colchicine, whereas 242 patients (57.8%) received RD colchicine. Lower BMI and estimated glomerular filtration rate, and higher incidence of cardiovascular disease were seen in the LD group than in the RD group. In IPTW-adjusted analysis, events of gout flare were not significantly different between the LD and RD groups [ITT: 14.3% vs 11.3%; odds ratio (OR): 1.309, 95% CI: 0.668, 2.566, P = 0.432; PP: 15.3% vs 10.0%; OR: 1.623, 95% CI: 0.765, 3.443, P = 0.207]. However, LD colchicine was associated with a lower rate of adverse events than RD colchicine [ITT: 8.2% vs 17.9%; OR: 0.410, 95% CI: 0.217, 0.777; P < 0.05; PP: 8.4% vs 17.2%; OR: 0.442, 95% CI: 0.223, 0.878; P < 0.05]. CONCLUSION: Our data suggest that LD colchicine can adequately prevent gout flare with fewer adverse events compared with RD colchicine.

Distinct neural networks associated with obsession and delusion: a connectome-wide association study.

BACKGROUND: Obsession and delusion are theoretically distinct from each other in terms of reality testing. Despite such phenomenological distinction, no extant studies have examined the identification of common and distinct neural correlates of obsession and delusion by employing biologically grounded methods. Here, we investigated dimensional effects of obsession and delusion spanning across the traditional diagnostic boundaries reflected upon the resting-state functional connectivity (RSFC) using connectome-wide association studies (CWAS). METHODS: Our study sample comprised of 96 patients with obsessive-compulsive disorder, 75 patients with schizophrenia, and 65 healthy controls. A connectome-wide analysis was conducted to examine the relationship between obsession and delusion severity and RFSC using multivariate distance-based matrix regression. RESULTS: Obsession was associated with the supplementary motor area, precentral gyrus, and superior parietal lobule, while delusion was associated with the precuneus. Follow-up seed-based RSFC and modularity analyses revealed that obsession was related to aberrant inter-network connectivity strength. Additional inter-network analyses demonstrated the association between obsession severity and inter-network connectivity between the frontoparietal control network and the dorsal attention network. CONCLUSIONS: Our CWAS study based on the Research Domain Criteria (RDoC) provides novel evidence for the circuit-level functional dysconnectivity associated with obsession and delusion severity across diagnostic boundaries. Further refinement and accumulation of biomarkers from studies embedded within the RDoC framework would provide useful information in treating individuals who have some obsession or delusion symptoms but cannot be identified by the category of clinical symptoms alone.

Lateral Size Effect of Graphene Oxide on Its Surface-Enhanced Raman Scattering Property.

The lateral size effect of graphene oxide (GO) on surfaced-enhanced Raman scattering (SERS) property is systematically investigated by using size-fractionalized GO. For the size fractionalization without changes of chemical structure, large-sized GO (LGO) and small-sized GO (SGO) are separated from the as-synthesized GO (AGO) by centrifugation and membrane filtration, respectively. The size-fractionalized GO sheets are immobilized on a solid substrate for the parallel comparison of their SERS property. As a result, we find that LGO shows considerably higher SERS property than SGO for typical Raman probes such as rhodamine 6G and crystal violet. Furthermore, the lateral size effect of GO derivatives is consistently observed when they are hybridized with plasmonic silver nanoparticles. These results indicate that LGO is superior to AGO and SGO as a SERS platform, and it is also quantitatively confirmed by calculating their enhancement factor.

Urine ß-2-glycoprotein 1 as a biomarker for diagnosis of systemic lupus erythematosus.

OBJECTIVE: The need for a biomarker with robust sensitivity and specificity in diagnosing systemic lupus erythematosus (SLE) remains unmet. Compared with blood samples, urine samples are more easily collected; thus, we aimed to identify such a biomarker based on urinary proteomics which could distinguish patients with SLE from healthy controls (HCs). METHODS: Urine samples were collected from 76 SLE patients who visited rheumatology clinic in 2019 at Asan medical center and from 25 HCs. Urine proteins were analyzed using sequential windowed acquisition of all theoretical fragment ion spectra-mass spectrometry, and the candidate marker was confirmed by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic curve analysis was used to determine the diagnostic value of the candidate biomarker. RESULTS: Of 1157 proteins quantified, 153 were differentially expressed in urine samples from HCs. Among them were previously known markers including α-1-acid glycoprotein 1, α-2-HS-glycoprotein, ceruloplasmin, and prostaglandin-H2 D-isomerase. Moreover, the amount of ß-2 glycoprotein (APOH) was increased in the urine of patients with SLE. The ELISA results also showed the level of urine APOH was higher in patients with SLE than in HCs and patients with rheumatoid arthritis. Moreover, the level was not different between SLE patients with and without nephritis. The urine APOH had an area under the curve value of 0.946 at a cut-off value of 228.53 ng/mg (sensitivity 91.5%, specificity 92.0%) for the diagnosis of SLE. CONCLUSION: The results indicate that the urine APOH level can be an appropriate screening tool in a clinical setting when SLE is suspected.