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Seong Shin Kwak,1,* Eun Seok Lee,1,* Ho Yub Yoon,1 Chang Hyun Kim,1 Yoon Tae Goo,1 Myung Joo Kang,2 Sangkil Lee,3 Bong Sang Lee,4 Hong Ryeol Jeon,4 Chang Hyun Oh,5 Young Wook Choi1 1College of Pharmacy, Chung-Ang University, Heuksuk-ro, Dongjak-gu, Seoul 06974, Republic of Korea; 2College of Pharmacy, Dankook University, Dandae-ro, Dongnam-gu, CheonanChungnam 31116, Republic of Korea; 3College of Pharmacy, Keimyung University, Dalgubeol-daero, Daegu 42601, Republic of Korea; 4CTCBIO INC., Hyundaikia-ro, Paltan, Hwaseong, Gyeonggi 18576, Republic of Korea; 5Center for Biomaterials, Korea Institute of Science & Technology (KIST), Hwarang-ro, Seongbuk-gu, Seoul 02792, Republic of Korea *These authors contributed equally to this work Purpose: To develop an immediate release-type tablet containing varenicline salicylate (VRC-S), a smoking cessation agent, formulation and stability studies were performed. The in vitro dissolution and in vivo pharmacokinetic (PK) behavior of the tablets were compared with those of the commercial product (Champix) as a reference. Materials and methods: The characteristics of the powder were investigated by particle morphology, size distribution, solubility, hygroscopicity, differential scanning calorimetry, and powder X-ray diffraction. Based on the drug–excipient compatibility test, different VRC-S tablets were prepared with the selected excipients through direct compression or wet granulation method and subjected to a dissolution test. The stability of the most promising VRC-S tablet (F4) was evaluated under accelerated conditions (40°C and 75% relative humidity). Further, the dissolution and human pharmacokinetic profiles of the F4 tablet and Champix were compared. Results: VRC-S showed a positively skewed unimodal size distribution with a specific surface area of 2.02 m2/g, single endothermic peak of 225.2°C in differential scanning calorimetry, crystalline internal structure in powder X-ray diffraction, aqueous solubility of 244.7 mg/mL, and hygroscopicity of 0.256 mg/g. The wet granulation method was preferred for tablet preparation and employed the following excipients: microcrystalline cellulose and anhydrous dibasic calcium phosphate as diluents, croscarmellose sodium as a disintegrant, and colloidal silicon dioxide and magnesium stearate as lubricants. The F4 tablet was stable for 6 months under accelerated conditions. The dissolution of VRC was pH independent, revealing f2 values of 76.49 and 68.38 at pH 1.2 and pH 6.8, respectively. After the oral administration of F4 tablet and Champix to healthy human volunteers, pharmacokinetic parameters, including time to reach the maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), and area under the curve from 0 to infinity (AUCinf), were compared. The values of 90% CI were 0.972–1.035 for Cmax and 0.982–1.075 for AUCinf, which was indicative of the bioequivalence of both products. Conclusion: VRC-S–containing F4 tablet might be a good candidate for smoking cessation treatment. Keywords: varenicline salicylate, smoking cessation, formulation, stability, dissolution, bioavailability

Dae Ro Lee,1 Myoung Jin Ho,1 Hyuck Jun Jung,1 Ha Ra Cho,1 Jun Seo Park,1 Suk-Hyun Yoon,2 Yong Seok Choi,1 Young Wook Choi,3 Chung-Hun Oh,2,4,5 Myung Joo Kang1 1College of Pharmacy, 2Department of Medical Laser, Graduate School, Dankook University, Dongnam-gu, Choenan, Chungnam, 3College of Pharmacy, Chung-Ang University, Dongjak-gu, Seoul, 4Department of Oral Physiology, College of Dentistry, Dankook University, 5Abel Medi-Tech Inc., Dongnam-gu, Cheonan, Chungnam, Korea Abstract: A new Soluplus (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer)-based supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to enhance oral absorption of tacrolimus (FK506) with minimal use of oil, surfactant, and cosurfactant. A high payload supersaturable system (S-SEDDS) was prepared by incorporating Soluplus, as a precipitation inhibitor, to SEDDS consisting of Capmul MCM, Cremophor EL, and Transcutol (FK506:vehicle:Soluplus =1:15:1). In vitro dissolution profile and in vitro pharmacokinetic aspect of S-SEDDS in rats were comparatively evaluated with those of conventional SEDDS formulas containing four times greater content of vehicle components (FK506:vehicle =1:60). Both formulations formed spherical drug-loaded microemulsion 80% of accumulated dissolution rate for 24 hours, analogous to that from conventional SEDDS. Moreover, pharmacokinetic parameters of the maximum blood concentration and area under the curve from S-SEDDS formula in rats were not statistically different (P>0.05) than those of conventional SEDDS. The results suggest that the Soluplus-based supersaturable system can be an alternative to achieve a comparable in vitro dissolution profile and in vivo oral absorption with conventional SEDDS, with minimal use of vehicle ingredients. Keywords: tacrolimus, supersaturation, precipitation inhibitor, Soluplus, microemulsion, oral bioavailability

In comparison with entanglement and Bell nonlocality, Einstein-Podolsky-Rosen steering is a newly emerged research topic and in its incipient stage. Although Einstein-Podolsky-Rosen steering has been explored via violations of steering inequalities both theoretically and experimentally, the known inequalities in the literatures are far from well-developed. As a result, it is not yet possible to observe Einstein-Podolsky-Rosen steering for some steerable mixed states. Recently, a simple approach was presented to identify Einstein-Podolsky-Rosen steering based on all-versus-nothing argument, offering a strong condition to witness the steerability of a family of two-qubit (pure or mixed) entangled states. In this work, we show that the all-versus-nothing proof of Einstein-Podolsky-Rosen steering can be tested by measuring the projective probabilities. Through the bound of probabilities imposed by local-hidden-state model, the proposed test shows that steering can be detected by the all-versus-nothing argument experimentally even in the presence of imprecision and errors. Our test can be implemented in many physical systems and we discuss the possible realizations of our scheme with non-Abelian anyons and trapped ions.

Abstract Background Patients with radiographic axial spondyloarthritis (r-axSpA) are at increased risk of incident cardiovascular events. Tumor necrosis factor inhibitors (TNFi) have shown a protective effect against incident cardiovacular events. However, the incidence of recurrent cardiovascular events in patients with r-axSpA with a history of cardiovascular events, and the effect of TNFi on recurrent cardiovascular events remain unclear. We aimed to assess the incidence rate of recurrent cardiovascular events in patients with r-axSpA with a history of cardiovascular events and evaluate the effect of TNFi on the risk of recurrent cardiovascular events. Methods This nationwide cohort study used data from the Korean National Claims Database. Data of patients with r-axSpA who had a history of cardiovascular events after being diagnosed with r-axSpA were extracted from the database. The outcome of interest was the recurrence of cardiovascular events (myocardial infarction or stroke). Patients were followed from the index date (date of the first cardiovascular event) to the date of cardiovascular event recurrence, the last date with claims data, or December 31, 2021, whichever occured first. The incidence rate of recurrent cardiovascular events was calculated. An inverse probability weighted Cox model was used to assess the effect of TNFi exposure on the risk of recurrent cardiovascular events. Results This study included 413 patients (TNFi non-exposure, n = 338; TNFi exposure, n = 75). The incidence rate of recurrent cardiovascular events was 32 (95% confidence interval [CI] 22–42) per 1,000 person-years (TNFi non-exposure, 36 [95% CI 24–48] per 1,000 person-years; TNFi exposure, 19 [95% CI 2–35] per 1,000 person-years). In the inverse probability weighted Cox model, TNFi exposure was significantly associated with a lower risk of recurrent cardiovascular events (hazard ratio 0.33, 95% CI 0.12–0.94). Conclusions The incidence rate of recurrent cardiovascular events in patients with r-axSpA is substantial. TNFi exposure was associated with a lower risk of recurrent cardiovascular events.

Abstract Background To assess the drug survival and change of disease activity using a second Janus kinase inhibitor (JAKi) after failure to a JAKi and subsequent biologic disease-modifying anti-rheumatic drugs (bDMARDs) in patients with difficult-to-treat rheumatoid arthritis (RA). Methods This retrospective cohort study included 32 patients with difficult-to-treat RA who failed to a JAKi and subsequently to one or more bDMARDs and then switched to a second JAKi. To assess drug survival, electronic medical records of each patient were reviewed. Data on whether the second JAKi was discontinued, and the reasons for discontinuation were collected. The change of disease activity was assessed by analyzing changes in tender joint count (TJC), swollen joint count (SJC), patient’s global assessment of disease activity on a visual-analogue scale (VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Disease Activity Score for 28 joints with ESR (DAS28-ESR), and DAS28-CRP from baseline to that at six months from initiation of the second JAKi. Results Overall, discontinuation of the second JAKi occurred in 20 (62.5%) patients. Primary failure, secondary failure, adverse events, and insurance coverage issues were the reasons for discontinuation in 9 (45.0%), 5 (25.0%), 2 (10.0%), and 4 (20.0%) patients, respectively. The estimated 2-year drug survival rate was 39.3%. In terms of change of disease activity, the second JAKi significantly improved TJC (p

Abstract Gamma-glutamyl transferase (GGT) is known to promote oxidative stress. As oxidative stress is a key component in the pathogenesis of systemic sclerosis (SSc), we investigated whether GGT levels are associated with the risk of incident SSc. A cohort of individuals without SSc who underwent national health examination in 2009 were extracted from the Korean National Health Insurance Service database. The incidence rate of SSc during the observation period, between 2009 and 2019, was estimated. GGT levels measured in 2009 were categorized into quartiles (Q1 [lowest], Q2, Q3, and Q4 [highest]). Multivariable Cox proportional hazard models were used to estimate the risk of incident SSc according to the quartiles of GGT, using Q1 as the reference. A total of 6,091,788 individuals were included. Incidence rate of SSc was 1.16 per 100,000 person-years over a mean observation period of 9.2 years. After adjusting for age, sex, body mass index, economic income, smoking status, alcohol consumption, physical activity, hypertension, type 2 diabetes, dyslipidemia, and chronic kidney disease, higher quartiles of GGT levels were significantly associated with a higher risk of incident SSc (Q4: adjusted hazard ratio [aHR] 1.807, 95% confidence interval CI 1.446–2.259; Q3: aHR 1.221, 95% CI 0.971–1.536; and Q2: aHR 1.034, 95% CI 0.807–1.324; p for trend

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by microdeletions in the long arm of chromosome 22. It is one of the most common chromosomal microdeletion disorders. Clinical symptoms are caused by heterozygous deletion of chromosome 22q11.2 and include congenital heart diseases and palatal abnormalities. Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder caused by deficiency of the glycoprotein Ib-IX-V complex (GPIb-IX-V), the receptor for von Willebrand factor. Glycoprotein Ib-beta (GPIbβ) gene mutation is one of the causes of BSS, and the GP1bβ gene is located on chromosome 22q11.2. Most 22q11DS patients do not have a bleeding issue since most of them have heterozygous deletion of the GPIbβ gene. However, we report a case in which a child with 22q11.2DS visited the hospital with subgaleal hemorrhage and was diagnosed with Bernard-Soulier syndrome with GPIbβ gene mutation by a platelet aggregation test and genetic sequencing.

ObjectiveAlthough the co-existence of systemic sclerosis (SSc) and psoriasis (PsO) has been reported, the risk relationship between the two diseases remains unclear. We aimed to assess whether SSc is associated with the risk of incident PsO.MethodsFrom the Korean National Health Insurance Service database, 4,933 patients with SSc and 24,665 age- and sex-matched controls were selected. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident PsO were estimated using multivariable Cox proportional hazard models adjusted for known risk factors of PsO. Further, we selected individuals whose health check-up data were available (2,355 patients with SSc and 11,775 age- and sex-matched controls). In this population, we further adjusted for additional risk factors of PsO using the health check-up data.ResultsIn the analysis of 4,933 patients with SSc and 24,665 age- and sex-matched controls, incidence rates of PsO in patients with SSc and controls were 10.26 and 3.20 per 1,000 person-years, respectively. After adjusting for risk factors of PsO, patients with SSc had a significantly higher risk of incident PsO (adjusted HR: 3.055 [95% CI: 2.597, 3.594]). Moreover, in the analysis of individuals who had health check-up data, additional risk factors of PsO were further adjusted; the result also showed that patients with SSc have a significantly higher risk of incident PsO (adjusted HR: 2.820 [95% CI: 2.207, 3.603]).ConclusionPatients with SSc had a 3-fold higher risk of developing incident PsO than controls, independent of known risk factors of PsO.

Objective Data from a decade ago have shown that patients with systemic sclerosis (SSc) have a higher risk of kidney failure than the general population. However, as the incidence of kidney failure due to SSc has been declining, the comparative risk of kidney failure between patients with SSc and the general population could have changed over time. We investigated the risk of kidney failure in patients with SSc compared with the general population, up to more recent years.Methods This was a nationwide population-based study using the Korean National Health Insurance Service database. Patients with claims data for SSc between 2010 and 2017 (n=2591) and 1:5 age-matched and sex-matched controls (n=12 955) were selected. The index date was the earliest date of claim for SSc between 2010 and 2017. The follow-up duration was from the index date to 2019. The adjusted HRs (aHRs) and 95% CI for kidney failure were estimated using multivariable Cox proportional hazard models.Results Over 5.2±2.6 years, the incidence rates of kidney failure in patients with SSc and controls were 2.88 and 0.35 per 1000 person-years, respectively. Patients with SSc had a significantly higher risk of kidney failure than controls (aHR=7.244, 95% CI=4.256 to 12.329). The effect size was larger in patients diagnosed with SSc between 2014 and 2017 (aHR=9.754, 95% CI=3.254 to 29.235) than in those diagnosed before 2010 (aHR=6.568, 95% CI=2.711 to 15.571) or between 2010 and 2013 (aHR=6.553, 95% CI=2.721 to 15.781).Conclusion The risk of kidney failure remains higher in patients with SSc than in the general population.

Abstract To estimate the risk of systemic lupus erythematosus (SLE) flares based on the autoantibody positivity at the time of SLE diagnosis. This retrospective cohort study included 228 patients with newly diagnosed SLE. Clinical characteristics including autoantibody positivity at the time of diagnosis of SLE were reviewed. Flares were defined as a new British Isles Lupus Assessment Group (BILAG) A score or BILAG B score for at least one organ system. Multivariable Cox regression analyses were performed to estimate the risk of flares according to autoantibody positivity. Anti-dsDNA, anti-Sm, anti-U1RNP, anti-Ro, and anti-La antibodies (Abs) were positive in 50.0%, 30.7%, 42.5%, 54.8%, and 22.4% of the patients, respectively. The incidence rate of flares was 28.2/100 person-years. Multivariable Cox regression analysis, adjusted for potential confounders, revealed that anti-dsDNA Ab positivity (adjusted hazard ratio [HR]: 1.46, p = 0.037) and anti-Sm Ab positivity (adjusted HR: 1.81, p = 0.004) at the time of diagnosis of SLE were associated with higher risk of flares. To better delineate the flare risk, patients were categorized as double-negative, single-positive, double-positive for anti-dsDNA and anti-Sm Abs. Compared with double-negativity, double-positivity (adjusted HR: 3.34, p

Abstract Both type 2 diabetes and immune-mediated inflammatory diseases (IMIDs), such as Crohn’s disease (CD), ulcerative colitis, rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis (PsO) are risk factors of cardiovascular disease. Whether presence of IMIDs in patients with type 2 diabetes increases their cardiovascular risk remains unclear. We aimed to investigate the risk of cardiovascular morbidity and mortality in patients with type 2 diabetes and IMIDs. Patients with type 2 diabetes without cardiovascular disease were retrospectively enrolled from nationwide data provided by the Korean National Health Insurance Service. The primary outcome was cardiovascular mortality, and the secondary outcomes were myocardial infarction (MI), stroke, and all-cause mortality. Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazard regression analysis was performed to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for each IMID. Overall 2,263,853 patients with type 2 diabetes were analyzed. CD was associated with a significantly higher risk of stroke (IPTW-adjusted HR: 1.877 [95%CI 1.046, 3.367]). UC was associated with a significantly higher risk of MI (1.462 [1.051, 2.032]). RA was associated with a significantly higher risk of cardiovascular mortality (2.156 [1.769, 2.627]), MI (1.958 [1.683, 2.278]), stroke (1.605 [1.396, 1.845]), and all-cause mortality (2.013 [1.849, 2.192]). AS was associated with a significantly higher risk of MI (1.624 [1.164, 2.266]), stroke (2.266 [1.782, 2.882]), and all-cause mortality (1.344 [1.089, 1.658]). PsO was associated with a significantly higher risk of MI (1.146 [1.055, 1.246]), stroke (1.123 [1.046, 1.205]) and all-cause mortality (1.115 [1.062, 1.171]). In patients with type 2 diabetes, concomitant IMIDs increase the risk of cardiovascular morbidity and mortality. Vigilant surveillance for cardiovascular disease is needed in patients with type 2 diabetes and IMIDs.

ObjectiveImmune-mediated inflammatory disease (IMID) is associated with an increased risk of mortality. It is unclear whether the higher mortality is attributable to the IMIDs themselves or to the higher prevalence of comorbidities in IMIDs. We aimed to investigate whether IMIDs per se confer a higher risk of mortality.MethodsFrom the Korean National Health Insurance Service-National Sample Cohort database, this population-based cohort study included 25,736 patients newly diagnosed with IMIDs between January 2007 and December 2017, and 128,680 individuals without IMIDs who were matched for age, sex, income, hypertension, type 2 diabetes, dyslipidemia, and the Charlson comorbidity index. All individuals were retrospectively observed through December 31, 2019. The outcomes included all-cause and cause-specific mortalities. Adjustments for age, sex, and comorbidities were performed using multivariable Cox proportional hazard regression analyses, and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the outcomes were estimated.ResultsThe adjusted risk of all-cause mortality was significantly lower in patients with IMIDs than that in those without (aHR, 0.890; 95% CI, 0.841–0.942). Regarding cause-specific mortality, cancer-specific (aHR, 0.788; 95% CI, 0.712–0.872) and cardiovascular disease-specific (aHR, 0.798; 95% CI, 0.701–0.908) mortalities were the two causes of death that showed significantly lower risks in patients with IMIDs. A similar trend was observed when organ based IMIDs were analyzed separately (i.e., gut, joint, and skin IMIDs).ConclusionAfter adjusting for comorbidities, IMIDs were associated with a lower risk of all-cause mortality compared to those without IMIDs. This was attributable to the lower risks of cancer-and cardiovascular disease-specific mortalities.

ObjectivePatients with type 2 diabetes (T2DM) are at a high risk of developing depression and anxiety. To better stratify the risk, we aimed to assess whether the presence of immune-mediated inflammatory diseases (IMIDs) confers a higher risk of depression and anxiety in these patients.MethodsPatients with T2DM without prior depression or anxiety who underwent national health examination between 2009 and 2012 (n = 1,612,705) were enrolled from the nationwide health check-up data from Korean National Health Insurance Service. The outcome events were incident depression and anxiety, defined as International Classification of Diseases, 10th Revision codes F32–F33 and F40–F41, respectively. Multivariable Cox proportional hazard regression analyses were conducted to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) according to the existence of IMIDs.ResultsOver an average follow-up time of 6.4 years, existence of gut IMIDs was associated with a higher risk of depression (aHR: 1.28 [95% CI: 1.08–1.53]) and anxiety (1.22 [1.06–1.42]). Existence of joint IMIDs was associated with a higher risk of depression (1.34 [1.31–1.37]) and anxiety (1.31 [1.29–1.34]). Existence of skin IMID was associated with a higher risk of depression (1.18 [1.14–1.23]) and anxiety (1.13 [1.09–1.16]). The effect sizes of IMIDs on depression and anxiety were larger in those with ≥ 2 IMIDs (1.42 [1.19–1.69] and 1.49 [1.29–1.72], respectively) than in those with one IMID (1.30 [1.27–1.32] and 1.26 [1.24–1.28], respectively).ConclusionIn patients with T2DM, presence of IMIDs was associated with a higher risk of depression and anxiety. More stringent attention and screening for anxiety and depression should be encouraged in patients with T2DM and comorbid IMIDs due to clinical implications of psychological distress on patient-reported outcomes and prognosis.

Abstract Background Axial spondyloarthritis (axSpA) is associated with an increased risk of cardiovascular disease. We aimed to evaluate the effect of tumor necrosis factor inhibitors (TNFis) on the risk of cardiovascular disease in patients with axSpA. Methods This retrospective study included 450 patients with axSpA without pre-existing cardiovascular disease. The outcome was incident cardiovascular disease (myocardial infarction or stroke) after the diagnosis of axSpA. The effect of TNFis on cardiovascular risk was analyzed in the total study population and in an inverse probability of treatment weighting (IPTW)-adjusted population. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for cardiovascular disease, according to exposure to TNFis. Results Of the 450 patients, 233 (51.8%) and 217 (48.2%) patients were and were not exposed to TNFis, respectively. Twenty cardiovascular diseases occurred during 2868 person-years of follow-up (incidence rate: 6.97/1000 person-years). In the total study population, exposure to TNFis was associated with a reduced cardiovascular risk when adjusted for traditional cardiovascular risk factors (HR 0.30, 95% CI 0.10–0.85, p = 0.024). However, when time-averaged erythrocyte sedimentation rate and C-reactive protein were additionally adjusted, this association was attenuated and lost statistical significance (HR 0.37, 95% CI 0.12–1.12, p = 0.077). Furthermore, in the IPTW-adjusted population, exposure to TNFis showed no significant reduction in cardiovascular risk (HR 0.60, 95% CI 0.23–1.54, p = 0.287). Conclusions Although controlling inflammation through TNFis could be beneficial in cardiovascular risk reduction, our data indicate no TNFi-specific reduction in cardiovascular risk in patients with axSpA.

BackgroundAssessing a patient’s suicide risk is challenging for health professionals because it depends on voluntary disclosure by the patient and often has limited resources. The application of novel machine learning approaches to determine suicide risk has clinical utility. ObjectiveThis study aimed to investigate cross-sectional and longitudinal approaches to assess suicidality based on acoustic voice features of psychiatric patients using artificial intelligence. MethodsWe collected 348 voice recordings during clinical interviews of 104 patients diagnosed with mood disorders at baseline and 2, 4, 8, and 12 months after recruitment. Suicidality was assessed using the Beck Scale for Suicidal Ideation and suicidal behavior using the Columbia Suicide Severity Rating Scale. The acoustic features of the voice, including temporal, formal, and spectral features, were extracted from the recordings. A between-person classification model that examines the vocal characteristics of individuals cross sectionally to detect individuals at high risk for suicide and a within-person classification model that detects considerable worsening of suicidality based on changes in acoustic features within an individual were developed and compared. Internal validation was performed using 10-fold cross validation of audio data from baseline to 2-month and external validation was performed using data from 2 to 4 months. ResultsA combined set of 12 acoustic features and 3 demographic variables (age, sex, and past suicide attempts) were included in the single-layer artificial neural network for the between-person classification model. Furthermore, 13 acoustic features were included in the extreme gradient boosting machine learning algorithm for the within-person model. The between-person classifier was able to detect high suicidality with 69% accuracy (sensitivity 74%, specificity 62%, area under the receiver operating characteristic curve 0.62), whereas the within-person model was able to predict worsening suicidality over 2 months with 79% accuracy (sensitivity 68%, specificity 84%, area under receiver operating characteristic curve 0.67). The second model showed 62% accuracy in predicting increased suicidality in external sets. ConclusionsWithin-person analysis using changes in acoustic features within an individual is a promising approach to detect increased suicidality. Automated analysis of voice can be used to support the real-time assessment of suicide risk in primary care or telemedicine.

Interleukin-32 (IL-32) is an important cytokine involved in the innate and adaptive immune responses. The role of IL-32 has been studied in the context of various diseases. A growing body of research has investigated the role of IL-32 in rheumatic diseases including inflammatory arthritides (rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and connective tissue diseases (systemic lupus erythematosus, systemic sclerosis, granulomatosis and polyangiitis, and giant cell arteritis). IL-32 has been shown to play different roles according to the type of rheumatic diseases. Hence, the putative role of IL-32 as a biomarker is also different in each rheumatic disease: IL-32 could serve as a biomarker for disease activity in some diseases, whereas in other diseases it could be a biomarker for certain disease manifestations. In this narrative review, we summarize the associations between IL-32 and various rheumatic diseases and discuss the putative role of IL-32 as a biomarker in each disease.

BackgroundDisease course of non-radiographic axial spondyloarthritis (axSpA) has been extensively studied in non-Asian population; however, there are limited data in Asian population. This study aimed to evaluate the long-term disease course of non-radiographic axSpA in Asian patients and identify factors associated with progression to radiographic axSpA.MethodsIn this retrospective observational cohort study, 56 Korean patients newly diagnosed with non-radiographic axSpA between 2006 and 2015 were included. All patients fulfilled the Assessment of SpondyloArthritis international Society classification criteria for axSpA, and did not fulfil the radiological criterion of the 1984 modified New York criteria. Disease course was assessed by the rate of progression to radiographic axSpA. Factors associated with the risk of progression to radiographic axSpA were assessed using multivariable Cox proportional hazard regression analysis.ResultsThe mean age at baseline was 31.4±13.3 years, and 37 (66.1%) patients were men. Over a mean observation period of 8.4±3.7 years, 28 (50.0%) patients progressed to radiographic axSpA. In multivariable Cox proportional hazard regression analysis, the presence of syndesmophytes at diagnosis (adjusted hazard ratio [HR]: 4.50, 95% confidence interval [CI]: 1.54-13.15, p = 0.006) and active sacroiliitis on magnetic resonance imaging (MRI) at diagnosis (adjusted HR: 5.88, 95% CI: 2.05-16.82, p = 0.001) were significantly associated with a higher risk of progression to radiographic axSpA, whereas longer exposure to tumor necrosis factor inhibitors (TNFis) was significantly associated with a lower risk of progression to radiographic axSpA (adjusted HR: 0.89, 95% CI: 0.80-0.98, p = 0.022).ConclusionDuring long-term follow-up, a substantial proportion of Asian patients with non-radiographic axSpA progressed to radiographic axSpA. The presence of syndesmophytes and active sacroiliitis on MRI at the time of non-radiographic axSpA diagnosis were associated with a higher risk of progression to radiographic axSpA, while longer exposure to TNFis was associated with a lower risk of progression to radiographic axSpA.

ObjectiveWe aimed to identify serologic parameters that correlate with the disease activity of IgG4-related disease (IgG4-RD) in patients with normal and elevated serum IgG4 concentrations, respectively.MethodsThis retrospective cohort study included 148 patients with IgG4-RD. Patients were categorized into normal (≤201 mg/dL) and elevated (>201 mg/dL) serum IgG4 concentration groups. Disease activity was assessed using the IgG4-RD responder index (RI). The correlations between IgG4-RD RI and serologic parameters (erythrocyte sedimentation rate [ESR], C-reactive protein, C3, C4, IgG4 concentration, IgG concentration, and IgG4/IgG ratio) were evaluated in each group, using Spearman’s correlation coefficient.ResultsOf the 148 patients with IgG4-RD, 38 (25.7%) and 110 (74.3%) patients were categorized into the normal and elevated serum IgG4 concentration groups, respectively. In the normal serum IgG4 concentration group, IgG concentration was the only serologic parameter that showed a significant correlation with IgG4-RD RI (rho=0.411, p=0.013). However, in the elevated serum IgG4 concentration group, ESR (rho=0.196, p=0.041), C3 (rho=-0.432, p

ObjectiveTo develop a new disease activity assessment tool with high accuracy for Takayasu arteritis.MethodsIndividual items from National Institute of Health (NIH) criteria and the Indian Takayasu Clinical Activity Score (ITAS2010) were tested as candidate variables to develop a new disease activity assessment tool in a derivation cohort (N = 100). Physician global assessment on disease activity was used as the gold standard. Multivariable logistic regression models were constructed and the model with the highest accuracy was identified. A formula assessing disease activity was generated using simplified β coefficients (rounded to decimal place). Diagnostic performance was evaluated through estimating the area under the curve (AUC). The new assessment tool was subsequently validated in a validation cohort (N = 46).ResultsThe multivariable model yielding the highest accuracy consisted of a high erythrocyte sedimentation rate (ESR), NIH criteria 1 and 4, and carotidynia. Using simplified β coefficients, the following disease activity assessment tool was developed: high ESR (3 points), NIH criterion 1 (2 points), NIH criterion 4 (4 points), and carotidynia (3 points) (total score ≥5, active; total score

Recent studies have demonstrated that the oral microbiome in patients with Sjögren’s syndrome (SS) is significantly different from that in healthy individuals. However, the potential role of the oral microbiome in SS pathogenesis has not been determined. In this study, stimulated intraductal saliva samples were collected from the parotid glands (PGs) of 23 SS and nine non-SS subjects through PG lavage and subjected to 16S ribosomal RNA amplicon sequencing. The correlation between the oral microbiome and clinical features, such as biological markers, clinical manifestations, and functional and radiological characteristics was investigated. The salivary microbial composition was examined using bioinformatic analysis to identify potential diagnostic biomarkers for SS. Oral microbial composition was significantly different between the anti-SSA-positive and SSA-negative groups. The microbial diversity in SS subjects was lower than that in non-SS sicca subjects. Furthermore, SS subjects with sialectasis exhibited decreased microbial diversity and Firmicutes abundance. The abundance of Bacteroidetes was positively correlated with the salivary flow rate. Bioinformatics analysis revealed several potential microbial biomarkers for SS at the genus level, such as decreased Lactobacillus abundance or increased Streptococcus abundance. These results suggest that microbiota composition is correlated with the clinical features of SS, especially the ductal structures and salivary flow, and that the oral microbiome is a potential diagnostic biomarker for SS.

Abstract Background To identify disease-specific factors associated with cardiovascular events in patients with Takayasu arteritis (TAK). Methods Patients with TAK who fulfilled the American College of Rheumatology 1990 criteria for the classification of TAK and were followed up between 2006 and 2019 were included. Traditional cardiovascular risk factors and TAK disease-specific factors at the index date and incident cardiovascular events during the follow-up were retrospectively assessed. To estimate the risk of cardiovascular events according to TAK disease-specific factors, Cox regression analysis with adjustment for traditional cardiovascular risk factors was performed. Results Of the total 207 patients with TAK, cardiovascular events occurred in 41 (19.8%) patients. Compared with patients who did not develop cardiovascular events, patients who developed cardiovascular events were older (38.5 ± 13.4 years vs. 43.6 ± 11.8 years, p = 0.028), more commonly had diabetes mellitus (6.6% vs. 19.5%, p = 0.029), had lower high-density lipoprotein cholesterol (57.3 ± 17.1 mg/dl vs. 51.2 ± 15.7 mg/dl, p = 0.040), more commonly had type V vascular involvement (33.1% vs. 63.4%, p 0.001), and less commonly received methotrexate (65.1% vs. 43.9%, p = 0.013). In Cox regression analysis, type V vascular involvement was significantly associated with increased risk of cardiovascular events (adjusted HR 2.852, 95% CI 1.474–5.518, p = 0.002), whereas the use of methotrexate was associated with reduced risk of cardiovascular events (adjusted HR 0.515, 95% CI 0.268–0.993, p = 0.047). Conclusion Type V vascular involvement was associated with increased risk of cardiovascular events, while the use of methotrexate was associated with reduced risk of cardiovascular events, in patients with TAK.

Abstract Background To investigate non-histologic factors that can discriminate proliferative lupus nephritis (LN) from membranous LN in patients with systemic lupus erythematosus with renal manifestations. Methods Patients with biopsy-proven proliferative LN (class III ± V and class IV ± V) and membranous LN (class V) were included. Non-histologic factors were compared between the two groups. A logistic regression analysis was performed to identify the factors associated with proliferative LN. To assess the accuracy of these factors in discriminating between proliferative LN and membranous LN, we performed a receiver-operating characteristic analysis. Results Of the total 168 patients with biopsy-proven LN, 150 patients (89.3%) had proliferative LN, and 18 patients (10.7%) had membranous LN. In the multivariable logistic regression analysis, positive anti-double-stranded DNA (anti-dsDNA) antibody (adjusted OR = 11.200, 95% CI = 2.202–56.957, p = 0.004) was associated with proliferative LN, while positive anti-U1RNP antibody (adjusted OR = 0.176, 95% CI = 0.040–0.769, p = 0.021) and higher glomerular filtration rate (GFR) (adjusted OR = 0.973, 95% CI = 0.951–0.994, p = 0.013) were inversely associated with proliferative LN. Among these covariates, the anti-dsDNA antibody (area under the curve = 0.806, 95% CI = 0.695–0.916) had the highest accuracy in discriminating between proliferative LN and membranous LN. Conclusion The positivity of anti-dsDNA antibody was associated with proliferative LN, while the positivity of anti-U1RNP antibody and GFR were inversely associated with proliferative LN. The anti-dsDNA antibody had a good accuracy in discriminating proliferative LN from membranous LN.

Background/Aims A substantial portion of gout patients have normal serum urate levels during an acute attack but data on the clinical characteristics and risk of recurrence compared with hyperuricemic patients are limited. Methods In this retrospective cohort study, clinical features of normouricemic and hyperuricemic patients were compared. Multivariate analysis was performed to determine whether normouricemic patients were less likely to have a recurrent attack. Results Among a total of 221 gout patients, 88 (39.8%) had normouricemia during an acute attack. Postsurgical gout (22.7% vs. 6.0%, p < 0.001), hemodialysis initiation (9.1% vs. 2.3%, p = 0.029) and inflammatory activity were higher in normouricemic patients than in hyperuricemic patients. The frequency of renal insufficiency was lower in normouricemic patients (25.0% vs. 53.4%, p < 0.001). However, the recurrence rate of gout attack was not different between the two groups (24.7% vs. 33.0%, p = 0.220). In multivariate analysis, female sex, history of urinary stone, presence of tophi, and use of thiazide were associated with increase of recurrent gout attack, but not with serum urate status during an acute attack (hazard ratio, 1.075; 95% confidence interval, 0.972 to 1.190; p = 0.159). Conclusions Normouricemia during an acute gout attack was more frequently observed in postsurgical episodes, hemodialysis initiation and patients with preserved renal function. While higher inflammatory activity was observed in normouricemic patients, recurrent attack was not associated with serum urate levels during an acute attack. Thus, careful follow-up should be considered in gout patients regardless of serum urate levels during an acute attack.

Introduction: To determine the cut-off values for age and symptom duration that could be used in selecting preferential first-line imaging modality of sacroiliac joints [X-ray versus magnetic resonance imaging (MRI)] for diagnosing axial spondyloarthritis (axSpA). Methods: This retrospective cohort study included 388 patients newly diagnosed with axSpA. Patients were classified into radiographic axSpA (n = 322) and non-radiographic axSpA (n = 66) groups according to the fulfilment of modified New York criteria by X-ray. Patient characteristics of the two groups were compared. Receiver operating characteristic (ROC) curve analysis was conducted to determine the cut-off values for age and symptom duration that best distinguish non-radiographic axSpA from radiographic axSpA. Results: Compared with patients with radiographic axSpA, those with non-radiographic axSpA were younger at diagnosis (35.7 ± 11.3 years versus 26.8 ± 7.8 years, p 33.5 years at diagnosis [area under the curve (AUC): 0.734] and symptom duration > 4.1 years (AUC: 0.787) were the cut-off values that best discriminate radiographic axSpA from non-radiographic axSpA. Conclusion: The best cut-off values for age and symptom duration for predicting radiographic sacroiliitis are 33.5 and 4.1 years, respectively. It is reasonable to use X-ray as a first-line imaging modality in patients older than 33.5 years with a symptom duration longer than 4.1 years, and use MRI as a first-line imaging in patients younger than 33.5 years with a symptom duration less than 4.1 years.

Shortfin scad (Decapterus macrosoma) is one of the most abundant catches of purse seiners in Bali strait. This study aimed to reveal the length-length relationship, the length-weight relationship, and to estimate the length at first maturity (Lm50) and the length at first capture (Lc50) for D. macrosoma in the waters of Bali Strait. The samples were collected from Pengambengan Fishing Port from June to December 2018. A total of 3,341 shortfin scads were fork length measured and weighed during the research. There were 420 fish from the total sample fish measured more for the total and standard length and dissected. The sex and maturation stage determination were identified by gonad visual characteristics. The relationship between lengths was determined using linear regression, whereas the length-weight relationship was determined using power regression. The length at first maturity and capture were determined using the logistic curve. The lengths (total, fork, and standard) were highly related to each other. The lengths were also highly related to the weight. The growth pattern of the shortfin scad was hyperallometric. The Lm50 for D. macrosoma was 164 mmTL for males and 162 mmTL for females. They were shorter than the Lc50, which was 184 mmTL.

The Emergency Medicine Recipes in Local Medicinals (Hyang’yak Kugŭpbang) (c. 14th century) is known to be one of the oldest Korean medical textbooks that exists in its entirety. This study challenges conventional perceptions that have interpreted this text by using modern concepts, and it seeks to position the medical activities of the late Koryŏ Dynasty (918-1392) to the early Chosŏn Dynasty (1392-1910) in medical history with a focus on this text. According to existing studies, Emergency Medicine Recipes in Local Medicinals is a strategic compromise of the Korean elite in response to the influx of Chinese medical texts and thus a medical text from a “periphery” of the Sinitic world. Other studies have evaluated this text as a medieval publication demonstrating stages of transition to systematic and rational medicine and, as such, a formulary book that includes primitive elements. By examining past medicine practices through “modern” concepts based on a dichotomous framework of analysis — i.e., modernity vs. tradition, center vs. periphery, science vs. culture — such conventional perceptions have relegated Emergency Medicine Recipes in Local Medicinals to the position of a transitional medieval publication meaningful only for research on hyangchal (Chinese character-based writing system used to record Korean during the Silla Dynasty [57 BC-935 AD] to the Koryŏ Dynasty). It is necessary to overcome this dichotomous framework in order to understand the characteristics of East Asian medicine. As such, this study first defines “medicine”, an object of research on medical history, as a “special form of problem-solving activities” and seeks to highlight the problematics and independent medical activities of the relevant actors. Through this strategy (i.e., texts as solutions to problems), this study analyzes Emergency Medicine Recipes in Local Medicinals to determine its characteristics and significance. Ultimately, this study argues that Emergency Medicine Recipes in Local Medicinals was a problem-solving method for the scholar-gentry from the late Koryŏ Dynasty to the early Chosŏn Dynasty, who had adopted a new cultural identity, to perform certain roles on the level of medical governance and constitute medical praxis that reflected views of both the body and materials and an orientation distinguished from those of the socalled medicine of Confucian physicians, which was the mainstream medicine of the center. Intertwined at the cultural basis of the treatments and medical recipes included in Emergency Medicine Recipes in Local Medicinals were aspects such as correlative thinking, ecological circulation of life force, transformation of materiality through contact, appropriation of analogies, and reasoning of sympathy. Because “local medicinals” is understood in Emergency Medicine Recipes in Local Medicinals as referring to objects easily available from one’s surroundings, it signifies locality referring to the ease of acquisition in local areas rather than to the identity of the state of Koryŏ or Chosŏn. As for characteristics revealed by this text’s methods of implementing medicine, Korean medicine in terms of this text consisted largely of single-ingredient formulas using diverse medicinal ingredients easily obtainable from one’s surroundings rather than making use of general drugs as represented by materia medica or of multipleingredient formulas. In addition, accessible tools, full awareness of the procedures and processes of the guidelines, procedural rituals, and acts of emergency treatment (first aid) were more important than the study of the medical classics, moral cultivation, and coherent explanations emphasized in categorical medical texts. Though Emergency Medicine Recipes in Local Medicinals can be seen as an origin of the tradition of emergency medicine in Korea, it differs from medical texts that followed which specializing in emergency medicine to the extent that it places toxicosis before the six climatic factors in its classification of diseases.

Outcome-Based Education (OBE) implementation is one of the qualifying requirements for engineering programme accreditation in Malaysia. Implementation of the OBE in Integrated Design Project (IDP) is essential in producing high quality engineering graduates that are able to meet the challenges especially in the era of Industry 4.0 in Malaysia. IDP is the course offered to the final year students of undergraduate programme in Faculty of Civil Engineering, University Teknologi MARA. This paper presents the mapping of the addressing Course Outcomes (CO) and Programme Outcomes (PO) to the scopes of assessment in a capstone project (CP) for IDP. The explicitness in the measurement of CO and PO in the course is demonstrated. The rubrics for the assessment of CP are also presented. Finally, evaluation of student performance in IDP particularly CP is discussed through a sample analysis of the CO and PO attainments.

Background: To investigate factors associated with drug survival of an alternative tumour necrosis factor inhibitor (TNFi) and secukinumab (SEC) after switching from the first TNFi in patients with ankylosing spondylitis (AS). Methods: We included a total of 78 patients with AS who switched to an alternative TNFi ( n = 56) or SEC ( n = 22) from the first TNFi. Patient characteristics at the time of switching and drug discontinuation rate were compared between the two groups. Cox regression analyses were performed to evaluate factors associated with the risk of discontinuing the alternative TNFi and SEC. Results: The proportion of patients with syndesmophytes was numerically lower (28.6% versus 45.5%, p = 0.155) and the C-reactive protein (CRP) level was numerically higher [3.8 (1.0–15.4) mg/L versus 1.1 (0.5–3.5) mg/L, p = 0.060] in patients who received an alternative TNFi. The drug discontinuation rate (alternative TNFi: 35.7% versus SEC: 36.4%, p = 0.957) and reasons for discontinuation were similar (primary failure, p = 0.342; secondary failure, p > 0.999; and adverse events, p = 0.670) between the two groups. A higher CRP level at switching was associated with a lower risk (adjusted HR = 0.93, 95% CI = 0.87–0.99, p = 0.022) of discontinuing the alternative TNFi, and primary failure of the first TNFi was associated with a higher risk [adjusted HR (HR) = 5.20, 95% confidence interval (CI) = 1.91–14.11, p = 0.001]. Current smokers (adjusted HR = 5.77, 95% CI = 1.20–27.74, p = 0.029) and the presence of syndesmophytes (adjusted HR = 7.49, 95% CI = 1.39–40.23, p = 0.019) were associated with a higher risk of discontinuing SEC. Conclusion: When switching the drug from the first TNFi in patients with AS, an alternative TNFi could be preferable in patients with higher CRP levels or syndesmophytes, or current smokers, whereas SEC could be a better choice in patients who presented primary failure of the first TNFi in terms of drug survival.

Background: To investigate factors associated with flare in patients with ankylosing spondylitis (AS) who tapered tumour necrosis factor inhibitors (TNFis) after achievement of low disease activity (LDA) with the standard dose of TNFis. Methods: This retrospective cohort study included 101 patients with AS who tapered their first TNFis after achievement of LDA. The proportion of reduced versus standard doses of TNFi throughout the follow up in each patient was quantified using the time-averaged dose quotient (DQ). Clinical characteristics were compared between patients who did and did not experience flare after TNFi tapering. Multivariable Cox regression analysis was performed to identify factors associated with flare. Receiver operating characteristic curve analysis was performed to determine the cut-offs of these covariates that best predicted flare. Results: Of the total 101 patients, 45 (44.6%) patients experienced flare after TNFi tapering. Compared with patients who did not experience flare, those who experienced flare had a shorter disease duration ( p = 0.006), shorter LDA duration before TNFi tapering ( p

Objectives: To assess the effect of vitamin D supplementation on bone mineral density (BMD) in rheumatoid arthritis (RA) patients with osteoporosis and determine whether supplementation of more than 800 IU/day, which is the currently recommended dose, is beneficial.Methods: RA patients with osteoporosis who received bisphosphonate were included. Patients were classified into four groups according to the dose of vitamin D supplementation (0, 400, 800, and ≥1,000 IU/day). Multivariable linear regression models were performed to evaluate the effect of each dose of vitamin D supplementation on 1-year% change of BMD.Results: In total, 187 RA patients with osteoporosis were included. In the multivariate model adjusted for potential confounders, patients receiving vitamin D supplementation had a significantly higher increase in 1-year % change in lumbar spine BMD (400 IU/day: β = 2.51 [95% CI: 0.04–4.99], 800 IU/day: β = 2.90 [95% CI: 0.47–5.33], and ≥1,000 IU/day: β = 6.01 [95% CI: 3.71–8.32]) and femoral neck BMD (400 IU/day: β = 3.88 [95% CI: 1.83–5.94], 800 IU/day: β =4.30 [95% CI: 2.25–6.35], and ≥1,000 IU/day: β = 6.79 [95% CI: 4.87–8.71]) than those not receiving the supplementation. Notably, the ≥1,000-IU/day group had a significantly higher increase in 1-year % change in lumbar spine BMD (β = 3.11 [95% CI: 0.86–5.37]) and femoral neck BMD (β = 2.50 [95% CI: 0.63–4.36]) than the 800-IU/day group.Conclusion: In RA patients with osteoporosis receiving bisphosphonates, vitamin D supplementation was associated with a higher increase in BMD. This effect was higher in the vitamin D supplementation dose of ≥1,000 IU/day than in 800 IU/day.

Abstract Background Takayasu arteritis (TAK) is a systemic disease characterized by large vessel involvement. Although the vascular characteristics of TAK are well characterized, there is no well-organized study demonstrating the extravascular manifestations of TAK. We aimed to evaluate the characteristics of extravascular manifestations of TAK, and to identify the association between vascular and extravascular manifestations of TAK. Methods TAK patients from two independent cohorts between January 2012 and October 2017 were included in the study. Patient characteristics were retrospectively collected from the electronic dataset. The computed tomography scans of all subjects were reviewed to evaluate the pattern of vascular involvement and presence of sacroiliitis. Clinical findings including uveitis, skin lesions, oral ulcers, arthritis, and inflammatory bowel disease (IBD) were reviewed. Logistic regression analysis was performed to evaluate the association between vascular and extravascular manifestations. Results For the 268 TAK patients, the mean age at diagnosis was 41.2 ± 14.2 years and 88.1% were female. The extravascular manifestation of TAK was observed in 19.0% of patients, the most common being arthritis including sacroiliitis (11.9%) followed by recurrent oral ulcers (8.6%) and IBD (2.6%). A multivariate logistic regression analysis revealed type IIB vascular involvement (adjusted odds ratio (OR) 2.956, 95% confidence interval (CI) 1.337–6.537, p = 0.007) and the erythrocyte sedimentation rate (ESR) (adjusted OR 1.014, 95% CI 1.003–1.025, p = 0.012) as significantly associated with the presence of axial and peripheral arthritis. Conclusions Extravascular manifestations of TAK were observed in up to one-fifth of patients. The most common extravascular manifestation was arthritis, which was associated with a type IIB vascular involvement pattern and a high ESR.

Objective: Uveitis is the most common extra-articular manifestation of ankylosing spondylitis (AS), for which no diagnostic biomarkers have been identified. This study was conducted to identify biomarker for uveitis in AS.Methods: To identify autoantibodies associated with uveitis in AS, we performed human protein microarray analysis using sera derived from various autoimmune diseases and ELISA analysis of sera derived from AS and rheumatoid arthritis patients. In the curdlan-induced SKG mice model, ophthalmic examination was performed at week 8 post-immunization and histologic examination of the ocular lesions performed at week 16 post-immunization. Serum levels of target antibodies were assessed at various time-points. To evaluate the functional role of specific autoantibodies, an in vitro apoptosis assay using ARPE-19 cells was performed.Results: Reactivity against prefoldin subunit 5 (PFDN5) was identified in AS with uveitis. Levels of anti-PFDN5 antibodies and PFDN5 in sera from AS with uveitis patients were significantly higher than those in AS without uveitis. At week 8, half of curdlan-treated SKG mice developed anterior uveitis, while all of them developed histologically confirmed uveitis at week 16. The levels of anti-PFDN5 antibodies increased over time in the sera of curdlan-treated SKG mice along with increased expression of PFDN5 and apoptosis in the ocular lesions. Knockdown of PFDN5 in ARPE19 cells resulted in increased apoptosis, suggesting a protective role of PFDN5 against cell death in uveitis.Conclusion: AS patients with uveitis have increased levels of anti-PFDN5 antibodies, and our findings suggest that anti-PFDN5 antibodies could provide a biomarker for uveitis in AS.

This paper presents a study on form-finding of four-stage class one self-equilibrated spine biotensegrity models. Advantageous features such as slenderness and natural curvature of the human spine, as well as the stabilizing network that consists of the spinal column and muscles, were modeled and incorporated in the mathematical formulation of the spine biotensegrity models. Form-finding analysis, which involved determination of independent self-equilibrium stress modes using generalized inverse and their linear combination, was carried out. Form-finding strategy for searching the self-equilibrated models was studied through two approaches: application of various combinations of (1) twist angles and (2) nodal coordinates. A total of three configurations of the spine biotensegrity models with different sizes of triangular cell were successfully established for the first time in this study. All members in the spine biotensegrity models satisfied the assumption of linear elastic material behavior. With the established spine biotensegrity model, the advantageous characteristics of flexibility and versatility of movement can be further studied for potential application in deployable structures and flexible arm in the robotic industry.

A phenomenological model describing the transverse energy distribution (ET) of nuclear collisions is first studied in detail by fitting it on ET data for O-Pb collisions at √sNN = 200 GeV per nucleon obtained from the NA35 collaboration. Next, the model is used to fit the ET data for Pb-Pb collisions at LHC energies of √sNN = 2.76 TeV per nucleon obtained from the ATLAS collaboration. From the fits, we determine an upper bound for the energy density for Pb-Pb collisions at LHC energies of √sNN = 2.76 TeV per nucleon.

We discuss an alternative picture of neutrino oscillation. In this phenomenological model, the flavor-changing phenomena of massless neutrinos arise from scattering processes between neutrinos and four types of undetected spin-0 massive particles pervading throughout the Universe, instead of neutrinos’ own nature. These scattering processes are kinematically similar to Compton scattering. One type of left-handed massless sterile neutrino is needed in order to reproduce the neutrino oscillation modes predicted in the theory of neutrino mixing. Implications of our model include the existence of sterile neu- trinos, the nonconservation of active neutrinos, the possible mismatch among three neutrino mass squared differences ∆m2ij interpreted in the theory of neutrino mixing, the spacetime dependence of neutrino oscillation, and the impossibility of neutrinoless double beta decay. Several important open problems in neutrino physics become trivial or less severe in our model, such as the smallness of neutrino masses, neutrino mass hierarchy, the mechanism responsible for neutrino masses, and the Dirac/Majorana nature of neutrinos.

A phenomenological model of particle production and hadronisation in high energy collisions is formulated using Dirac fields in Yukawa-like interaction and the resulting stochastic equation is solved numerically. Different initial conditions are used to compare particle- particle (ψ ψ) and particle-antiparticle (ψ* ψ) interactions. It is shown that in this simplified view, there is a clear difference between the final multiplicity distributions resulting from the two initial conditions. To model the restricted phase space (limited pseudorapidity) measurements in experiment, a “loss” function is also proposed to account for the undetected particles close to the beam line.

Neutrino oscillations are a possible way to probe beyond Standard Model physics. The propagation of Dirac neutrinos in a massive medium is governed by the Dirac equation modified with an effective Hamiltonian that de- pends on the number density of surrounding matter fields. At the same time, quantum nonlinearities may contribute to neutrino oscillations by further mod- ifying the Dirac equation. A possible nonlinearity is computationally studied using Mathematica at low energies. We find that the presence of a uniform, static background matter distribution may significantly alter the oscillation am- plitude and wavelength; the considered nonlinearity may further reduce both oscillation amplitude and wavelength. In addition, the presence of matter al- lows the effects of the nonlinearity to be more readily observed for the chosen background densities and neutrino energy.

ObjectiveTo gain a better understanding of the pathogenesis of autoimmune arthritis-associated interstitial lung disease (ILD), we sought to identify the characteristics of lung-infiltrating cells in SKG mice with ILD.MethodsWe injected curdlan in SKG mice at 8 weeks of age, and identified the presence of ILD by PET-MRI at 20 weeks post-injection and histological analysis at 22 weeks post-injection. Lung-infiltrating cells were examined by flow cytometry. Analysis of serum cytokines by the Luminex multiplex cytokine assay was performed at 14 and 22 weeks post-injection, and cytokine profiles before and after the development of ILD were compared. Opal multiplexed immunofluorescent staining of lung tissue was also performed.ResultsAt 20 weeks post-injection, curdlan-treated SKG mice developed not only arthritis but also lung inflammation combined with fibrosis, which was identified by PET-MRI and histological analysis. The majority of inflammatory cells that accumulated in the lungs of curdlan-treated SKG mice were CD11b+Gr1+ neutrophils, which co-express IL-17A and GM-CSF, rather than TNF-α. Compared with 14 weeks post-injection, serum levels of GM-CSF, MCP1, IL-17A, IL-23, TSLP, and soluble IL-7Rα had increased at 22 weeks post-injection, whereas those of IFN-γ, IL-22, IL-6, and TNF-α remained unchanged. Furthermore, IL-23, CXCL5, IL-17A, and GM-CSF, but not TNF-α, were observed in immunofluorescent-stained lung tissue.ConclusionWe found that IL-17A+GM-CSF+ neutrophils represented the major inflammatory cells in the lungs of curdlan-treated SKG mice. In addition, GM-CSF and IL-17A appear to play a more important role than TNF-α in ILD development.

It has been suggested that inflammasome-mediated IL-1β production in monocytic cells is responsible for the acute inflammatory response in gouty arthritis. However, phenotypical and functional analyses of monocytes during gouty arthritis have yet to be conducted. Therefore, we investigated the characteristics of monocytes/macrophages in the synovial fluid cells of patients with acute gout. The number and frequency of monocytes/macrophages in the synovial fluid mononuclear cells (SFMCs) of patients was examined. The expression of markers for monocyte recruitment and tissue-resident macrophages, the production of pro-inflammatory and anti-inflammatory cytokines, and phagocytosis were analyzed in the monocytes/macrophages of patients with acute gout attacks. The number and frequency of CD14+CD3−CD19−CD56− monocytes/macrophages was markedly increased in the SFMCs of patients with gout compared to those of patients with rheumatoid arthritis (RA). CD14+ cells showed the phenotypes of infiltrated monocytes rather than tissue-resident macrophages, characterized by a high expression of CCR2, MRP8, and MRP14, but a low expression of MERTK and 25F9. These cells had the capacity to produce pro-inflammatory cytokines such as TNF-α and IL-1β after stimulation with lipopolysaccharides. In addition, anti-inflammatory features, including CD163 expression and IL-10 production from CD14+ cells, were significantly higher in patients with gout than in those with RA. CD14+ cells with phenotype of M2 macrophages had high phagocytic activity for monosodium urate crystals. Thus, our results indicate that monocytes/macrophages from patients with gout have the phenotype of infiltrated monocytes, and these cells consist of different populations characterized by anti-inflammatory activities as well as pro-inflammatory functions.