OBJECTIVES:Although 1H-nuclear magnetic resonance (NMR)-based lipid/metabolomics has been used to detect atherosclerosis, data regarding lipid/metabolomic signature in rheumatoid arthritis (RA)-related atherosclerosis are scarce. We aimed to identify the distinct lipid/metabolomic profiling and develop a prediction score model for RA patients with subclinical atherosclerosis (SA).METHODS:Serum levels of lipid metabolites were determined using 1H-NMR-based lipid/metabolomics in 65 RA patients and 12 healthy controls (HCs). The occurrence of SA was defined as the presence of carotid plaques revealed in ultrasound images.RESULTS:Compared with HC, RA patients had significantly higher levels of phenylalanine and glycoprotein acetyls (GlycA) and lower levels of leucine and isoleucine. RA patients with SA had significantly higher levels of phenylalanine, creatinine, and glycolysis_total and lower levels of total lipid in HDL(HDL_L) than RA patients without SA. The Lasso logistic regression analysis revealed that age, creatinine, HDL_L, and glycolysis_total were significant predictors for the presence of SA. The prediction scoring algorithm was built as ( -0.657 + 0.011*Age + 0.004*Creatinine -0.120*HDL_L + 0.056*glycolysis-related measures), with AUC 0.90, sensitivity 83.3%, and specificity 87.2%. Serum phenylalanine levels were significantly decreased, and the levels of HDL_L and HDL_Particle were significantly increased in 20 RA patients, paralleling the decrease in disease activity score for 28-joints.CONCLUSIONS:With 1H-NMR-based lipid/metabolomics, distinct profiling of lipid metabolites was identified between RA patients and HC or between RA patients with and without SA. We further developed a scoring model based on lipid/metabolomics profiling for predicting RA-associated SA.

OBJECTIVES:Monocyte distribution width (MDW) correlates with volume modifications of circulating monocytes upon activation. Given the crucial role of monocyte activation in the pathogenesis of adult-onset Still's disease (AOSD), we aimed to examine the associations between MDW and disease activity or inflammatory parameters in this disease.METHODS:In 58 AOSD patients and 95 other patients with coronavirus disease 2019 (COVID-19) as disease control, MDW and complete blood count were determined using a UniCel DxH800 analyser. C-reactive protein (CRP) levels were measured by nephelometry, and ferritin levels by chemiluminescent immunoassay. AOSD activity was assessed using a modified Pouchot score.RESULTS:MDW was significantly higher in active AOSD patients (median 28.3, interquartile range [IQR] 23.3-32.1) compared with inactive AOSD (19.2, IQR 18.0-20.6, p<0.001) or non-severe COVID-19 patients (23.2, IQR 21.0-25.2, p<0.01). MDW was positively correlated with AOSD activity scores, CRP, and ferritin levels (all p<0.001). Longitudinal follow-up evaluation revealed that median MDW significantly declined (28.3 versus 18.5, p<0.001) along with disease activity, paralleling a decrease in CRP and ferritin levels. Severe COVID-19 and sepsis patients had elevated MDW, which were not different from active AOSD patients. Multivariate analysis revealed MDW as a significant predictor of active AOSD, and MDW threshold at 21.7 could predict an active status with a high sensitivity of 91.3% and specificity of 94.3%.CONCLUSIONS:Elevated MDW and its positive correlation with inflammatory parameters in AOSD patients indicate MDW as a novel activity indicator, with a high MDW value above 21.7 linked to a high probability of active AOSD.

OBJECTIVES Adult-onset Still's disease (AOSD) is a rare and complex inflammatory disease with unclear immunopathogenesis. This study aims to investigate the expression signature of inflammation-associated long non-coding RNAs (lncRNAs) in AOSD and to evaluate its utility for disease diagnosis and prognostication. METHODS Expression levels of lncRNAs MIAT, THRIL, NTT, RMRP, PACERR and NEAT1 in peripheral blood mononuclear cells (PBMCs) from treatment-naïve AOSD patients and healthy donors were assessed by quantitative real-time PCR and logistic regression analysis. RESULTS A diagnostic scoring algorithm was built based on the expression pattern of MIAT, THRIL and RMRP, which could differentiate AOSD from patients with rheumatoid arthritis, systemic lupus erythematosus, or sepsis. Our score could also predict the need of biologics in AOSD treatment. We further followed up ten AOSD patients and found that the expression of NEAT1 was positively correlated with the expression levels of MIAT, THRIL and RMRP after treatment. In poly(I:C)-stimulated THP-1 cell and primary monocytes, MIAT upregulation coupled with THRIL downregulation was similar to the expression pattern observed in AOSD. CONCLUSIONS Our study provides an AOSD diagnostic scoring system based on the expression signature of MIAT, THRIL and RMRP. Further investigations are needed to uncover the mechanisms of lncRNA dysregulation in AOSD.

Objective: Sodium benzoate, a D-amino acid oxidase (DAAO) inhibitor, improved cognitive function of early-phase Alzheimer’s disease (AD) after 24-week treatment. This study examined benzoate treatment for behavioral and psychological symptoms of dementia (BPSD). Methods: In a double-blind, 6-week trial, 97 patients with BPSD were randomized to receive placebo or benzoate (mean dose: 622.0 mg/day). The primary outcomes were ADAS-cog and BEHAVE-AD. Results: Two treatments showed similar safety and primary and secondary outcomes. Conclusions: Compared to antecedent 24-week, higher-dose treatment for early-phase AD, benzoate appeared ineffective in this 6-week trial. Longer-duration, higher-dose trials are warranted to clarify its efficacy for BPSD.

Background and purposePhysical activity is associated with a reduced incidence of first‐time stroke. However, few studies have examined the effect of pre‐stroke physical activity on post‐stroke complications and clinical outcomes.MethodsA total of 39 835 cases of stroke registered in the nationwide stroke registry system of Taiwan between 2006 and 2009 were analyzed according to five levels of severity as determined by National Institutes of Health Stroke Scale score upon hospital admission. Pre‐stroke physical activity was defined in the Taiwan Stroke Registry as dedicated leisure‐time physical activity for at least 30 min/day for 3 days/week for more than 6 months. A Cox model was used to compare complications and outcomes between active and inactive groups.ResultsThe active and inactive groups were similar in age distribution and stroke type distribution, but the active group had better National Institutes of Health Stroke Scale scores upon admission. The active group also had significantly fewer post‐stroke complications. Active patients had lower hospital mortality and better functional outcomes upon discharge as per the modified Rankin Scale. Improved functional status in the active group was significant at 1, 3 and 6 months post‐stroke.ConclusionDedicated leisure‐time physical activity for at least 30 min/day, at least three times per week for more than 6 months was associated with decreased stroke severity, fewer post‐stroke complications, lower mortality and better outcomes.

To delineate the differences in clinical characteristics and evaluate the outcome between primary and secondary cough headache, 83 consecutive patients (59M/ 24F, mean age 61.5 ± 17.7 years) with cough headache (1.2%) out of 7100 patients in a headache clinic were studied. All of them received brain imaging studies. Most did not have relevant brain lesions ( n = 74, 89.2%, primary group) except for nine patients (10.8%, the secondary group). Most of the intracranial lesions were located in the posterior fossa ( n = 6, 67%), including only two patients with Chiari malformation. The primary group had a higher response rate to indomethacin than the secondary group (72.7% vs. 37.5 %, P = 0.046). Mild to moderate headache intensity and age onset < 50 years predicted a favourable response. At a mean follow-up of 51.4 months, 83.9% of patients with primary cough headache completely remitted. Inconsistent with the proposed International Classification of Headache Disorders, 2nd edn criteria, 10.8% of patients with primary cough headache had headache duration of > 30 min. Clinical features, neurological examinations and drug response could not safely differentiate primary from secondary cough headache. Neuroimaging studies are required in each patient.

BACKGROUND:Adjunctive fluvoxamine inhibits clozapine metabolism and decreases plasma norclozapine (a toxic metabolite of clozapine) to clozapine ratios. This study aimed to demonstrate the effects of fluvoxamine on clozapine-related weight gain, hyperglycemia, and lipid abnormalities.METHOD:Sixty-eight treatment-resistant inpatients with a DSM-IV diagnosis of schizophrenia were randomly assigned to 2 treatment groups for 12 weeks. The monotherapy group (N = 34) received clozapine (< or = 600 mg/day). The coadministration group (N = 34) received fluvoxamine (50 mg/day) plus low-dose clozapine (< or = 250 mg/day). The study was conducted from August 1999 to October 2002.RESULTS:The 2 groups were similar in demographic data; baseline body weight and body mass index (BMI); baseline serum glucose, triglyceride, and cholesterol levels; and steady-state plasma clozapine concentration. The monotherapy patients (but not the coadministration patients) had significantly higher (p < .05) body weight, BMI, and serum glucose and triglyceride levels after treatment than at baseline. At week 12, the monotherapy patients also had significantly higher glucose (p = .035), triglyceride (p = .041), and norclozapine (p = .009) (and numerically higher cholesterol) levels than the cotreatment patients. The changes in weight and serum glucose and triglyceride levels were significantly correlated (p = .026, p = .005, and p = .028, respectively) with the plasma concentration of norclozapine but not with plasma levels of clozapine.CONCLUSION:These results suggest that fluvoxamine cotreatment can attenuate weight gain and metabolic disturbances in clozapine-treated patients. Plasma levels of norclozapine, but not clozapine, are associated with increases in weight and serum glucose and triglyceride levels. Of note, coadministration of fluvoxamine could increase plasma clozapine levels markedly and carry the risk of adverse events. If this combined treatment is applied, conservative introduction with reduced clozapine dosage and careful therapeutic drug monitoring of clozapine concentration is recommended.

BACKGROUND:Concomitant fluvoxamine use can potentially reduce the dosage of clozapine needed in treatment-refractory patients with schizophrenia. Previous reports have shown that fluvoxamine can increase plasma clozapine concentrations by inhibition of cytochrome P450 (CYP) 1A2. We evaluated the safety and efficacy of fluvoxamine, 50 mg/day, coadministration with clozapine, 100 mg/day, in refractory schizophrenic patients.METHOD:In this prospective study, 18 treatment-refractory patients with DSM-IV schizophrenia (10 nonsmokers and 8 smokers) were treated with clozapine at a target dose of 100 mg h.s. After steady-state conditions of clozapine had been reached, 50 mg/day of fluvoxamine was then added. Plasma levels of clozapine, norclozapine, and clozapine N-oxide were measured prior to fluvoxamine addition and on days 14 and 28 during combined treatment. Side effects and efficacy were monitored with standardized rating instruments.RESULTS:After 14 days of combined treatment, the mean +/- SD plasma clozapine level increased 2.3-fold to 432.4+/-190.9 ng/mL without further elevation on day 28. All patients completed the study without significant adverse side effects. Twelve of the 18 patients achieved plasma clozapine concentrations of at least 350 ng/mL. While plasma norclozapine levels also rose (but to a smaller extent), plasma clozapine N-oxide levels remained unchanged after the add-on therapy. Patients who smoked had 34% lower plasma clozapine concentrations than nonsmokers (NS). Three of the 4 patients who did not reach clozapine plasma levels of at least 300 ng/mL were smokers. Plasma norclozapine/clozapine ratios, especially in smokers, declined significantly with fluvoxamine addition.CONCLUSION:The addition of fluvoxamine, 50 mg/day, to low-dose clozapine, 100 mg/day, can raise plasma clozapine levels to at least 300 ng/mL in most patients. Only slight dosage adjustments with clozapine may be needed after fluvoxamine coadministration in some patients who smoke. Plasma clozapine levels remained stable after 14 days of fluvoxamine addition. The combined treatment was well tolerated, and clinical improvement was observed in our patients. Further long-term studies with this drug combination are needed to determine its economic impact.