The Taiwanese Map of Axial Spondyloarthritis: Living with the Condition.

Background and Objective: The International Map of Axial Spondyloarthritis (IMAS) explores the physical, psychological, and social experiences of patients with axial spondyloarthritis (axSpA). This initiative is now being expanded to Taiwan as the Taiwanese Map of Axial Spondyloarthritis (TMAS). We aim to provide rheumatologists with insights into the perspectives of Taiwanese patients, enabling physicians to better understand the unmet needs of these patients and optimize their management. Materials and Methods: The TMAS is a cross-sectional study gathering data through an online survey of axSpA patients, promoted by the Ankylosing Spondylitis Caring Society of R.O.C. (ASCARES), conducted from July 2017 to March 2018 by Ipsos, and analyzed by the Health & Territory Research (HTR) group of the University of Seville. The questionnaire includes 99 questions that cover domains such as patient profile, diagnosis, habits/lifestyle, employment status, physical/psychological health status, social support, use of healthcare services, and treatments. Results: A total of 112 axSpA patients were included in this survey. The mean age was 38.6 years and 75.0% were male. The average diagnostic delay was 3 years, and 19.6% reported extra-articular manifestations. Out of the 49 respondents who reported HLA-B27 information, 35 were HLA-B27-positive. The disease burden was high, with a mean BASDAI score of 4.9 and 75.9% having a mild to moderate degree of spinal stiffness. Furthermore, they were socially and psychologically burdened, with 88.4% experiencing work-related issues and 25.9% suffering from anxiety. Conclusions: The TMAS sheds light on the overall perspective of axSpA patients in Taiwan. The TMAS shows shorter diagnostic delay compared to patients from the EMAS. However, high disease activity and significant psychological distress still trouble the patients, causing functional impairments and even leading to career failures. Understanding the perspective of axSpA patients can help rheumatologists adjust treatment strategies to their unmet needs and improve their disease outcomes.

Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis.

Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA-anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause inflammation. The activated complements in the IC act as chemoattractants to chemically attract both innate and adaptive immune cells to the kidney tissues, causing inflammatory reactions. However, recent investigations have unveiled that not only the infiltrating immune-related cells, but resident kidney cells, including glomerular mesangial cells, podocytes, macrophage-like cells, tubular epithelial cells and endothelial cells, may also actively participate in the inflammatory and immunological reactions in the kidney. Furthermore, the adaptive immune cells that are infiltrated are genetically restricted to autoimmune predilection. The autoantibodies commonly found in SLE, including anti-dsDNA, are cross-reacting with not only a broad spectrum of chromatin substances, but also extracellular matrix components, including α-actinin, annexin II, laminin, collagen III and IV, and heparan sulfate proteoglycan. Besides, the glycosylation on the Fab portion of IgG anti-dsDNA antibodies can also affect the pathogenic properties of the autoantibodies in that α-2,6-sialylation alleviates, whereas fucosylation aggravates their nephritogenic activity. Some of the coexisting autoantibodies, including anti-cardiolipin, anti-C1q, anti-ribosomal P autoantibodies, may also enhance the pathogenic role of anti-dsDNA antibodies. In clinical practice, the identification of useful biomarkers for diagnosing, monitoring, and following up on LN is quite important for its treatments. The development of a more specific therapeutic strategy to target the pathogenic factors of LN is also critical. We will discuss these issues in detail in the present article.

2023 Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) Joint Consensus on Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH), defined as the presence of a mean pulmonary artery pressure > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of PAH proposed worldwide. Objectives: This study aimed to obtain a comprehensive understanding and provide recommendations for the management of CTD-PAH in Taiwan, focusing on its clinical importance, prognosis, risk stratification, diagnostic and screening algorithm, and pharmacological treatment. Methods: The members of the Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) reviewed the related literature thoroughly and integrated clinical trial evidence and real-world clinical experience for the development of this consensus. Conclusions: Early detection by regularly screening at-risk patients with incorporations of relevant autoantibodies and biomarkers may lead to better outcomes of CTD-PAH. This consensus proposed specific screening flowcharts for different types of CTDs, the risk assessment tools applicable to the clinical scenario in Taiwan, and a recommendation of medications in the management of CTD-PAH.

NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression.

Signaling driven by nucleic acid sensors participates in interferonopathy-mediated autoimmune diseases. NLRP12, a pyrin-containing NLR protein, is a negative regulator of innate immune activation and type I interferon (IFN-I) production. Peripheral blood mononuclear cells (PBMCs) derived from systemic lupus erythematosus (SLE) patients expressed lower levels of NLRP12, with an inverse correlation with IFNA expression and high disease activity. NLRP12 expression was transcriptionally suppressed by runt-related transcription factor 1-dependent (RUNX1-dependent) epigenetic regulation under IFN-I treatment, which enhanced a negative feedback loop between low NLRP12 expression and IFN-I production. Reduced NLRP12 protein levels in SLE monocytes was linked to spontaneous activation of innate immune signaling and hyperresponsiveness to nucleic acid stimulations. Pristane-treated Nlrp12-/- mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12-deficient lupus-prone mice. NLRP12 deficiency mediated the increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function. These were bound in an IFN-I signature-dependent manner in the mouse models. Collectively, we reveal a remarkable link between low NLRP12 expression and lupus progression, which suggests the impact of NLRP12 on homeostasis and immune resilience.

Effectiveness of salt substitute on cardiovascular outcomes: A systematic review and meta-analysis.

Hypertension-related death is the leading cause of mortality worldwide, making blood pressure (BP) control an important issue. Salt substitute is a non-pharmaceutical strategy to improve hypertension control. The goal of this study was to evaluate the effect of salt substitute on BP and cardiovascular disease. The authors searched the Cochrane Library and PubMed databases through March 2022, and assessed the risk-of-bias for included studies by the Cochrane risk-of-bias tool. Twenty-three randomized controlled trials with 32073 patients were included in our systematic review. A meta-analysis with random effects was performed to analyze the effects of salt substitute on systolic and diastolic BP, 24-h urinary sodium and potassium, and cardiovascular and all-cause mortality. In the random-effects model, participants consuming salt substitute showed significant reduction in systolic BP (mean difference (MD) -4.80 mmHg, 95% confidence interval (CI) -6.12 to -3.48, P < 0.0001) and diastolic BP (MD -1.48 mmHg, 95% CI -2.06 to -0.90, P < 0.0001) compared with participants consuming normal salt. In the urine electrolyte analysis, the salt substitute group had significant reduction in 24-h urine sodium (MD -22.96 mmol/24-h, P = 0.0001) and significant elevation in 24-h urine potassium (MD 14.41 mmol/24-h, P < 0.0001). Of the five studies with mortality outcome data, salt substitute significantly reduced all-cause mortality (hazard ratio 0.88, P = 0.0003). In conclusion, our analyses showed that salt substitute has a strong effect on lowering BP and reducing all-cause mortality. By modifying the daily diet with salt substitute, the authors can improve BP control by using this non-pharmaceutical management.

Implementing a flipped classroom model in an evidence-based medicine curriculum for pre-clinical medical students: evaluating learning effectiveness through prospective propensity score-matched cohorts.

BACKGROUND: In a flipped classroom (FC) model, blended learning is used to increase student engagement and learning by having students finish their readings at home and work on problem-solving with tutors during class time. Evidence-based medicine (EBM) integrates clinical experience and patient values with the best evidence-based research to inform clinical decisions. To implement a FC and EBM, students require sufficient information acquisition and problem-solving skills. Therefore, a FC is regarded as an excellent teaching model for tutoring EBM skills. However, the effectiveness of a FC for teaching EBM competency has not been rigorously investigated in pre-clinical educational programs. In this study, we used an innovative FC model in a pre-clinical EBM teaching program. METHODS: FC's teaching was compared with a traditional teaching model by using an assessment framework of prospective propensity score matching, which reduced the potential difference in basic characteristics between the two groups of students on 1:1 ratio. For the outcome assessments of EBM competency, we used an analysis of covariance and multivariate linear regression analysis to investigate comparative effectiveness between the two teaching models. A total of 90 students were prospectively enrolled and assigned to the experimental or control group using 1:1 propensity matching. RESULTS: Compared with traditional teaching methods, the FC model was associated with better learning outcomes for the EBM competency categories of Ask, Acquire, Appraise, and Apply for both written and oral tests at the end of the course (all p-values< 0.001). In particular, the "appraise" skill for the written test (6.87 ± 2.20) vs. (1.47 ± 1.74), p < 0.001), and the "apply" skill for the oral test (7.34 ± 0.80 vs. 3.97 ± 1.24, p < 0.001) had the biggest difference between the two groups. CONCLUSIONS: After adjusting for a number of potential confunding factors, our study findings support the effectiveness of applying an FC teaching model to cultivate medical students' EBM literacy.

Real-world effectiveness and safety of golimumab in rheumatoid arthritis treatment: A two-center study in Taiwan.

BACKGROUND: The real-world outcomes of golimumab (GLM) use have been rarely studied in Asian patients with rheumatoid arthritis (RA). This study assessed the real-world effectiveness and safety of GLM in a Taiwanese cohort. METHODS: One hundred and eight GLM-treated RA patients were enrolled. Predictors of a good European League Against Rheumatism (EULAR) response at 24 months and drug retention were identified through multivariate analyses. RESULTS: After 24 months of GLM treatment, the mean Disease Activity Score using 28 joint counts with the erythrocyte sedimentation rate (DAS28-ESR) decreased from 6.7 to 3.1 (p < 0.001). Up to 58.9% of patients achieved a good EULAR response at 24 months. Multivariate logistic regression analysis revealed that after adjustment for other variables, a higher baseline C-reactive protein was an independent negative predictor of good EULAR responses (odds ratio, 0.82; 95% confidence interval [CI], 0.67-0.99; p = 0.043). During the mean follow-up period of 38.3 months, 15 (13.9%) patients discontinued GLM due to treatment failure. In multivariate analysis, high baseline ESR level, high DAS28-ESR, and the experience of biologic therapy were independent risk factors for GLM discontinuation (adjusted hazard ratio [HR], 1.03; 95% CI, 1.01-1.05; p = 0.003; adjusted HR, 2.93; 95% CI, 1.42-6.08; p = 0.004; and adjusted HR, 5.00; 95% CI, 1.75-14.26; p = 0.003, respectively). In receiver operator characteristic curve analysis, the optimal cutoff values of baseline ESR and DAS28-ESR for predicting drug survival were 52 mm/h (sensitivity: 60.0% and specificity: 77.4%) and 7.7 (sensitivity: 46.7% and specificity: 94.3%), respectively. During the follow-up period, 22 patients (20.4%) developed adverse events. The safety profile of GLM in this study was comparable with that in previous clinical trials. CONCLUSION: GLM was effective and safe for the real-life management of Taiwanese RA patients and showed a high retention rate in biologic-naive patients compared with biologic-experienced patients.

Pneumocystis Jirovecii Pneumonia in Systemic Lupus Erythematosus: A Nationwide Cohort Study in Taiwan.

OBJECTIVE: To evaluate Pneumocystis jirovecii pneumonia (PJP) infection risk in patients with systemic lupus erythematosus (SLE) in Taiwan. METHODS: We identified 24,367 patients with SLE from the National Health Insurance research database between 1997 and 2012 and compared the PJP incidence rates (IRs) with those in 243,670 age- and sex-matched non-SLE controls. PJP risk in the patients was evaluated using a Cox multivariate proportional hazards model. RESULTS: The SLE patients exhibited a significantly higher PJP risk than the controls, with an IR of 2.63 per 10,000 person-years and IR ratio of 27.65 (95% confidence interval 17.2-45.3; P < 0.001). Male sex (hazard ratio [HR] 2.42, P < 0.01), end-stage renal disease (ESRD; HR 1.74, P = 0.01), recent use of mycofenolate mofetil (MMF; HR 4.43, P < 0.001), intravenous steroid pulse therapy (HR 108.73, P < 0.001), and average oral dosage of >7.5 mg/day prednisolone or equivalent treatment (HR 4.83, P < 0.001) were associated with PJP in SLE, whereas hydroxychloroquine use reduced its risk (HR 0.51, P = 0.01). Of note, cyclophosphamide was not associated with PJP infection in the multivariate Cox proportional hazard model. CONCLUSION: Patients with SLE have a considerably high PJP risk. Cyclophosphamide does not increase PJP risk. Male sex, ESRD, MMF use, intravenous steroid pulse therapy, and oral prednisolone or equivalent treatment (>7.5 mg/day) are risk factors for PJP, whereas hydroxychloroquine use reduces PJP risk.

Epidemiology and risk of invasive fungal infections in systemic lupus erythematosus: a nationwide population-based cohort study.

INTRODUCTION: Infections are a leading cause of mortality in patients with systemic lupus erythematosus (SLE). Among various infections, invasive fungal infections (IFIs) have a particularly high mortality rate; however, studies examining IFIs in patients with SLE are limited. METHODS: Patients diagnosed as having SLE between 1997 and 2012 were enrolled from Taiwan's National Health Insurance Research Database along with age- and sex-matched non-SLE controls at a ratio of 1:10. IFIs were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification codes and validated by the prescriptions of systemic antifungal agents. The incidence rate (IR), incidence rate ratio (IRR), and all-cause mortality rate of IFIs and its subtypes were analyzed. A Cox multivariate regression model with time-dependent covariates was applied to analyze independent risk factors for IFIs. RESULTS: A total of 24,541 patients with SLE and 245,410 non-SLE controls were included. We observed 445 IFI episodes in the SLE cohort, with an all-cause mortality rate of 26.7%. Candida spp. (52.8%) was the most common pathogen, followed by Cryptococcus spp. (18.2%) and Aspergillus spp. (18.2%). The IR of IFIs in the SLE cohort was 20.83 per 10,000 person-years, with an IRR of 11.1 [95% confidence interval (CI): 9.8-12.6] relative to the non-SLE controls. Juvenile patients with SLE aged ⩽18 years had the highest IRR of 47.2 (95% CI: 26.9-86.8). Intravenous steroid therapy administered within 60 days (hazard ratio: 29.11, 95% CI: 23.30-36.37) was the most critical risk factor for overall IFIs and each of the three major fungal pathogens. Distinct risk factors were found among different IFI subtypes. CONCLUSION: Patients with SLE had a higher risk of IFIs, especially juvenile patients. Intravenous steroid therapy is the most critical risk factor for IFIs. This study provides crucial information for the risk stratification of IFIs in SLE. PLAIN LANGUAGE SUMMARIES: Patients with systemic lupus erythematosus and physicians treating this patient group should be aware of the risk of invasive fungal infections.Invasive fungal infections (IFIs) are a severe complication with a high mortality rate among patients with systemic lupus erythematosus (SLE); however, studies on this topic are scant. We performed a nationwide population-based study in Taiwan to estimate the incidence and mortality of and risk factors for IFIs. We found an incidence rate of 20.83 per 10,000 person-years for IFIs, with a mortality rate of 26.7%. Juvenile patients aged ⩽18 years had the highest relative risk of IFIs. Although candidiasis was the most common IFI, cryptococcosis and aspergillosis should be concerned in juvenile patients as well. Intravenous steroid therapy was the most critical risk factor for all IFIs, and different immunosuppressive agents posed different risks in patients for acquiring certain fungal pathogens.Our findings provide pivotal epidemiological information and indicate risk factors for IFIs in patients with SLE. Age and exposure to specific immunosuppressants and steroids might help predict the risk of IFIs. Because the manifestation of these infections is sometimes indistinguishable from a lupus flare, physicians should be aware of this fatal complication, especially when patients are not responsive to immunosuppressive therapy. Early recognition, implication of diagnostic tools, and empirical antimicrobial agents can be the key to treating patients with IFIs. Additional studies are required to develop a risk management program for patients with SLE.

Periodontal conditions in patients with Sjögren's syndrome: A meta-analysis.

Sjögren's syndrome (SS) is a chronic autoimmune rheumatic disease characterized by a progressive lymphocytic infiltration of salivary glands, resulting in xerostomia and other oral diseases. The pathogenesis and mechanisms of SS on periodontal tissues are not well understood. Furthermore, results of two systemic reviews and meta-analyses in which compared periodontal parameters of patients with SS to healthy subjects were different. To determine whether periodontal conditions in SS were different from healthy controls, we re-examined the issue with a random-effect model, avoiding recruiting active controls and inadequate data conversion. Outcome measures included probing pocket depth (PPD), clinical attachment loss (CAL), plaque index (PI), and gingival index (GI). Recruited individuals comprised 198 patients with SS and 180 subjects for healthy controls. Quantitative analysis revealed higher PI (WMD = 0.76, 95% CI: 0.30, 1.23) and GI (WMD of total = 0.50, 95% CI: 0.01, 0.98) in SS patients who were not categorized into primary or secondary types of SS. PPD and CAL in SS patients was comparable with control subjects. However, heterogeneity was observed among included studies. Thus, results from this and previous analyses should be interpretated carefully, and a well-designed observational study regarding this issue should be conducted.

The prevalence and risk factors of sarcopenia in rheumatoid arthritis patients: A systematic review and meta-regression analysis.

BACKGROUND: Sarcopenia is an ever-increasingly recognized entity in aging or chronically-ill individuals. A recent surge of researches came out on sarcopenia in rheumatoid arthritis (RA). However, the results varied widely. We tried to assess the prevalence of and associated factors with sarcopenia in patients with RA. METHODS: We searched the investigations dealing with the prevalence of and associated factors with sarcopenia in RA from PubMed, EMBASE, CENTRAL, EBSCOhost, Airiti Library, CEPS, CNKI and J-STAGE from the inception to January 11, 2020. Effects regarding prevalence and associated factors were extracted and evaluated by random-effects model. Sensitivity analysis was also performed. RESULTS: Seventeen studies containing 3,140 RA subjects were identified. After exclusion of outliers, the pooled prevalence of sarcopenia was 31%. Neither ongoing-study districts nor diagnostic modalities affected prevalence significantly. Any associated factors being mentioned in at least two publications were analyzed, yielding functional limitation (Steinbrocker stage III/IV), high CRP and RF seropositivity as the significant risk factors. Based on disease durations, we carried out meta-regression and found DAS28 and HAQ are predictive models. There was no alteration in the interpretation of results from sensitivity analysis after removal of any studies skewed in sampling distribution. CONCLUSIONS: The prevalence of sarcopenia in patients with RA is high, compared to that in general counterparts. Disease duration rather than age, residing area or diagnostic modalities influences sarcopenia development; DAS28 and HAQ predict occurrence. High index of suspicion to facilitate early detection of sarcopenia in RA patients is important.

Cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) suppresses Staphylococcus aureus-induced CD80, CD86, and pro-inflammatory cytokine expression in human B cells.

BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) competes with CD28 for binding CD80/CD86 on antigen-presenting cells (APCs) to limit T cell activation. B cells are believed to be important APCs in the pathogenesis of autoimmune diseases and express CD80/CD86 after activation; however, relatively little is known about the effect of CTLA-4-Ig on B cells. This study tested the impact of CTLA-4-Ig on human B cell responses. METHODS: Human blood B cells were purified from healthy donors and activated in the presence of CTLA-4-Ig or the L6-Ig control protein in vitro. RT-q-PCR and immunofluorescence staining were performed to detect activation marker expression. ELISA was conducted to measure cytokine secretion. The CD80/CD86 levels on the surface of the memory B cells in the blood of 18 patients with rheumatoid arthritis (RA) were detected using immunofluorescence staining. RESULTS: CTLA-4-Ig suppressed the expression of Staphylococcus aureus (SAC)-induced CD80, CD86, TNFA, and IL6 in human B cells at the transcriptional level. Furthermore, CTLA-4-Ig concomitantly decreased SAC-induced CD80/CD86 surface expression on and TNF-α and IL-6 secretion from B cells. On the other hand, T cell-dependent (TD) stimulation-induced B cell activation, proliferation, plasma cell differentiation, and antibody secretion were not affected by CTLA-4-Ig. As expected, TD stimulation-induced surface CD80 was hindered by CTLA-4-Ig. Notably, a blockade of CD80/CD86 on the surface of the memory B cells was observed in the patients with RA after abatacept (CTLA-4-Ig) treatment. In a portion of the RA patients, restoration of CD80/CD86 staining on the surface of the memory B was detected starting in the 3rd month of abatacept treatment. Interestingly, the surface levels of CD80/CD86 on the patients' memory B cells positively correlated with disease activity. CONCLUSIONS: We found that CTLA-4-Ig directly suppressed SAC-induced B cell activation in vitro. Obstruction of CD80 and CD86 on the surface of the memory B cells was detected in the RA patients after abatacept treatment. Blocking CD80/CD86 on B cells by CTLA-4-Ig may hinder T cell activation and associated with the disease activity of RA in vivo. Our findings indicate that CTLA-4-Ig may regulate humoral responses by modulating B cell activation and interfering T cell-B cell interaction.

Risk of severe herpes simplex virus infection in systemic lupus erythematosus: analysis of epidemiology and risk factors analysis in Taiwan.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) are susceptible to herpes simplex virus (HSV) infection, which occasionally leads to severe complications including meningoencephalitis and keratitis. However, few attempts to analyse the associated incidence and risk factors have been made. METHODS: We enrolled patients with SLE recorded between 1997 and 2012 and compared the incidence rate (IR) of severe HSV infection, including meningoencephalitis, septicaemia, ocular and visceral involvement, and other specific complications demanding hospitalisation, with that of a non-SLE cohort. A Cox multivariate proportional hazards model was applied to analyse the risk factors of severe HSV infection in patients with SLE. RESULTS: A total of 122 520 subjects (24 504 patients with SLE and 98 016 age-matched and sex-matched non-SLE controls) were included, and a higher IR of severe HSV infection was revealed in the SLE group (IR ratio=3.93, p<0.001). In patients with SLE, previous oral and genital infection (HR=2.29, p=0.049), intravenous steroid pulse therapy (HR=5.32, p<0.001) and daily oral dose of over 7.5 mg of prednisolone (HR=1.59, p=0.024) were independent risk factors for severe HSV infection, whereas age of ≤18 (HR=0.45, p=0.029) was a protective factor. CONCLUSIONS: Patients with SLE are at higher risk of severe HSV infection, and related risk factors include being older than 18 years, having a history of HSV mucocutaneous infection, recent receipt of steroid pulse therapy and a daily oral dose of steroid over 7.5 mg prednisolone.

NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25.

Establishing the balance between positive and negative innate immune mechanisms is crucial for maintaining homeostasis. Here we uncover the regulatory crosstalk between two previously unlinked innate immune receptor families: RIG-I, an anti-viral cytosolic receptor activated type I interferon production, and NLR (nucleotide-binding domain, leucine repeat domain-containing protein). We show that NLRP12 dampens RIG-I-mediated immune signaling against RNA viruses by controlling RIG-I's association with its adaptor MAVS. The nucleotide-binding domain of NLRP12 interacts with the ubiquitin ligase TRIM25 to prevent TRIM25-mediated, Lys63-linked ubiquitination and activation of RIG-I. NLRP12 also enhances RNF125-mediated, Lys48-linked degradative ubiquitination of RIG-I. Vesicular stomatitis virus (VSV) infection downregulates NLRP12 expression to allow RIG-I activation. Myeloid-cell-specific Nlrp12-deficient mice display a heightened interferon and TNF response and are more resistant to VSV infection. These results indicate that NLRP12 functions as a checkpoint for anti-viral RIG-I activation.

Self- and rater-assessed effectiveness of "thinking-aloud" and "regular" morning report to intensify young physicians' clinical skills.

BACKGROUND: This study compared the effects of the "thinking aloud" (TA) morning report (MR), which is characterized by sequential and interactive case discussion by all participants, with "regular" MR for clinical skill training of young physicians. METHODS: Between February 2011 and February 2014, young physicians [including postgraduate year-1 (PGY1) residents, interns, and clerks) from our hospital were sequentially enrolled and followed for 3 months. The self- and rater-assessed educational values of two MR models for building up clinical skills of young physicians were compared. RESULTS: The junior (intern and clerk) attendees had higher self-assessed educational values scores and reported post-training application frequency of skills trained by TA MR compared with the senior (PGY1 resident) attendees. Higher average and percentage of increased overall rater-assessed OSCE scores were noted among the regular MR senior attendees and TA MR junior attendees than in their corresponding control groups (regular MR junior attendees and TA MR senior attendees). Interestingly, regular MRs provided additional beneficial effects for establishing the "professionalism, consulting skills and organization efficiency" aspects of clinical skills of senior/junior attendees. Moreover, senior and junior attendees benefited the most by participating in seven sessions of regular MR and TA MR each month, respectively. CONCLUSION: TA MR effectively trains junior attendees in basic clinical skills, whereas regular MR enhances senior attendees' "work reports, professionalism, organizational efficiency, skills in dealing with controversial and professional issues." Undoubtedly, all elements of the two MR models should be integrated together to ensure patient safety and good discipline among young physicians.

PML protein as a prognostic molecular marker for patients with esophageal squamous cell carcinomas receiving primary surgery.

BACKGROUND AND OBJECTIVES: We evaluated the clinicopathological associations and prognostic implications of promyelocytic leukemia gene (PML) expressions in patients with esophageal squamous cell carcinomas (ESCC) receiving primary surgery. METHODS: Expression patterns of PML and tumor protein 53 (TP53) of 132 cases of ESCC were evaluated by immunohistochemistry and correlated with clinicopathological parameters. The Cox proportional hazards model was used to determine the prognostic influence of clinicopathological factors on progression-free survival (PFS) and overall survival (OS). RESULTS: Forty-two cases (31.82%) were classified as lost expression of PML, 25 (18.94%) as focally positive, and 65 (49.24%) as diffusely expressed. Sixty-three cases (47.73%) were classified as over-expression of TP53. High expression of TP53 and down-regulation of PML were often found in advanced disease; and, in together with high pathological staging, grading, and positive margin, were associated with poor survival. However, only tumor differentiation (P = 0.016), distant metastasis (P = 0.001), and PML expression (P = 0.001) could act as independent prognostic factors for PFS, and LN metastasis (P = 0.004), TP53 (P = 0.006), and PML expression (P = 0.029) were identified as independent prognostic factors for OS in multivariate analysis. CONCLUSIONS: Our study demonstrated PML protein as an independent prognostic marker for patients with ESCC receiving primary surgery.