Author Correction: Bile acid metabolites control TH17 and Treg cell differentiation.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Bile acid metabolites control TH17 and Treg cell differentiation.

Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (TH17 cells) or regulatory T cells (Treg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of TH17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-γt (RORγt) and isoalloLCA increased the differentiation of Treg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of Treg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase Treg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced TH17 cell differentiation and increased Treg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of TH17 and Treg cells.

Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring.

Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder. In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (TH17) cells (CD4+ T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA. However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote TH17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal TH17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells from pregnant, but not from non-pregnant, females secrete IL-1ß, IL-23 and IL-6 and stimulate T cells to produce IL-17a upon exposure to MIA. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce TH17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes.

Differences in the risk of mood disorders in patients with asthma-COPD overlap and in patients with COPD alone: a nationwide population-based retrospective cohort study in Korea.

BACKGROUND: Although feelings of anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), little is known about the estimates of their incidence in patients with asthma-COPD overlap (ACO), which has been described and acknowledged as a distinct clinical entity. We aimed to estimate the risk of depression and anxiety among patients with ACO and compare it with the risk among those with COPD alone in the general population. METHODS: We conducted a nationwide population-based retrospective cohort study using the Korean National Sample Cohort database between 1 January, 2002, and 31 December, 2013. Patients who were diagnosed with COPD (International Classification of Diseases, 10th revision [ICD-10] codes J42-J44) at least twice and prescribed COPD medications at least once between 2003 and 2011 were classified into two categories: patients who were diagnosed with asthma (ICD-10 codes J45-J46) more than twice and at least once prescribed asthma medications comprised the ACO group, and the remaining COPD patients comprised the COPD alone group. Patients who had been diagnosed with depression or anxiety within a year before the index date were excluded. We defined the outcome as time to first diagnosis with depression and anxiety. Matched Cox regression models were used to compare the risk of depression and anxiety among patients with ACO and patients with COPD alone after propensity score matching with a 1:1 ratio. RESULTS: After propensity score estimation and matching in a 1:1 ratio, the cohort used in the analysis included 15,644 patients. The risk of depression during the entire study period was higher for patients with ACO than for patients with COPD alone (adjusted hazard ratio, 1.10; 95% confidence interval, 1.03-1.18; P value = 0.0039), with an elevated risk in patients aged 40-64 years (1.21; 1.10-1.34; 0.0001) and in women (1.18; 1.07-1.29; 0.0005). The risk of anxiety was higher for patients with ACO than for patients with COPD alone (1.06; 1.01-1.12; 0.0272), with a higher risk in patients aged 40-64 years (1.08; 1.00-1.17; 0.0392); however, the risk was not significant when stratified by sex. CONCLUSIONS: This population-based study revealed a higher incidence of depression and anxiety in patients with ACO than in patients with COPD alone.

Experience of advance directives in a hospice center.

To protect patient autonomy when confronting death, the importance of advance directives (ADs) has recently became an issue and gradually accepted in Korea. However, in real practice, ADs were not completed by patients but their families in most cases. To analyze the current situation of performing ADs, we reviewed medical charts of 214 terminal cancer patients admitted to the hospice center from October 2012 to September 2013. Seventy-six (35.5%) patients completed ADs. All ADs were completed by patients themselves. The most common reason for not completing ADs was poor physical and/or mental condition. As a proxy, the majority of patients preferred their spouses (55.3%). Few patients wanted life sustaining treatment (1.3%), however palliative sedation was accepted in 89.5%. The median timing of ADs after admission was three (0-90) days, and duration of survival since ADs was 22 (1-340) days. In conclusion, approximately one third of terminal cancer patients completed ADs by themselves. Considering that patient's poor condition is the main reason for not completing ADs, earlier discussion regarding ADs is necessary to enhance patients' participation.

Value-Based Pricing and Budget Impact Analysis for Multi-Indication Drugs: A Case Study of Immunotherapies.

We aimed to calculate the value-based price of each indication and compare the drug price and budget impact among value-based pricing (VBP) scenarios, using immunotherapy as a case. Atezolizumab, nivolumab, and pembrolizumab prices were estimated for VBP scenarios, namely indication value-based pricing (IBP), IBP with refund, and weighted-average pricing (WAP). To estimate the value-based price of each indication, cost-effectiveness analyses were conducted by setting the incremental cost-effectiveness ratio of the first reimbursed indication to the threshold. The budget impact for each scenario was compared with that of the pricing system in Korea (which has a 4.75% price reduction). The value-based prices of non-reimbursed indications were lower for atezolizumab and higher for nivolumab than those for the reimbursed indication. The drug price fluctuations were the largest in IBP, varying between 28.56-328.81% of the current list price. The net price of the non-reimbursed indications decreased from 0% to 71.44% in IBP with refund, and the budget impact was the lowest among VBPs. Although the fluctuation in the budget impact in WAP was smaller than IBP, higher drug prices were identified for low-value indications. In conclusion, IBP with refund is a viable method for multi-indication drugs, because it has minimal drug price and budget impact changes.

Efficacy of teicoplanin in bloodstream infections caused by Enterococcus faecium: posthoc analysis of a nationwide surveillance.

OBJECTIVES: Vancomycin and teicoplanin are glycopeptides with activity against Enterococcus faecium. However, studies on the clinical efficacy of teicoplanin are limited. This study aimed to compare the therapeutic efficacy of teicoplanin and vancomycin in E. faecium bacteremia. METHODS: We identified patients with bloodstream infections prospectively from July 2015 to December 2016 in 14 hospitals as part of a multicenter nationwide surveillance. Patients with E. faecium monomicrobial bacteremia were selected. Teicoplanin and vancomycin groups included patients treated with either agent for ≥48 hours. The primary outcome was 30-day all-cause in-hospital mortality. The Cox proportional hazards model with inverse probability weighting was used to account for the imbalance in baseline characteristics between the two groups. RESULTS: Among 97 patients with E. faecium bacteremia, 33 (34%) were treated with teicoplanin and 64 (66%) with vancomycin. There were no significant differences in 30-day in-hospital mortality (18.2% vs 26.6%, P = 0.358) and 7-day mortality (6.1% vs 15.6%, P = 0.212). Furthermore, multivariable analysis confirmed that the use of teicoplanin was not significantly associated with mortality (adjusted odds ratio, 0.72; 95% confidence interval, 0.28-1.86; P = 0.494). CONCLUSION: We found no significant differences in the clinical outcomes. These findings suggest teicoplanin as a useful alternative to vancomycin.

Severity-Adjusted Dexamethasone Dosing and Tocilizumab Combination for Severe COVID-19.

PURPOSE: Real-world experience with tocilizumab in combination with dexamethasone in patients with severe coronavirus disease (COVID-19) needs to be investigated. MATERIALS AND METHODS: A retrospective cohort study was conducted to evaluate the effect of severity-adjusted dosing of dexamethasone in combination with tocilizumab for severe COVID-19 from August 2020 to August 2021. The primary endpoint was 30-day clinical recovery, which was defined as no oxygen requirement or referral after recovery. RESULTS: A total of 66 patients were evaluated, including 33 patients in the dexamethasone (Dexa) group and 33 patients in the dexamethasone plus tocilizumab (DexaToci) group. The DexaToci group showed a statistically significant benefit in 30-day clinical recovery, compared to the Dexa group (p=0.024). In multivariable analyses, peak FiO2 within 3 days and tocilizumab combination were consistently significant for 30-day recovery (all p<0.05). The DexaToci group showed a significantly steeper decrease in FiO2 (-4.2±2.6) than the Dexa group (-2.7±2.6; p=0.021) by hospital day 15. The duration of oxygen requirement was significantly shorter in the DexaToci group than the Dexa group (median, 10.0 days vs. 17.0 days; p=0.006). Infectious complications and cellular and humoral immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the convalescence stage were not different between the two groups. CONCLUSION: A combination of severity-adjusted dexamethasone and tocilizumab for the treatment of severe COVID-19 improved clinical recovery without increasing infectious complications or hindering the immune response against SARS-CoV-2.

Comparative Cost-Effectiveness of Tofacitinib With Continuing Conventional Synthetic Disease-Modifying Anti-Rheumatic Drugs for Active Rheumatoid Arthritis in South Korea.

INTRODUCTION: The objective of this study was to evaluate the cost-effectiveness of initiating treatment with tofacitinib and subsequently incorporating it into a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) treatment sequence and to compare the cost-effectiveness of this sequence with that of continuing csDMARDs alone in patients with active rheumatoid arthritis (RA). METHODS: A cohort-based Markov model was used to evaluate the cost-effectiveness of two tofacitinib treatment sequences compared with that of continuing the csDMARD treatment sequence over a lifetime. Of the two tofacitinib sequences, the first consisted of initial tofacitinib treatment followed by biologic DMARDs (bDMARDs) and the second consisted of csDMARD treatments followed by tofacitinib. A third treatment sequence, continuing the csDMARD treatment sequence before starting bDMARDs, was used as a comparator. Efficacy was assessed using the American College of Rheumatology (ACR) response rates (ACR 20, ACR 50, and ACR 70) after 6 months, which were converted to changes in the health assessment questionnaire-disability index (HAQ-DI) score. Utility was estimated by mapping from the HAQ-DI score, costs were analyzed from a Korean societal perspective, and outcomes were considered in terms of quality-adjusted life-years (QALYs). One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the model. RESULTS: The incremental cost-effectiveness ratios over a lifetime for starting with tofacitinib and incorporating tofacitinib into the csDMARD treatment sequence versus continuing csDMARDs only were US$14,537 per QALY and US$7,086 per QALY, respectively. One-way sensitivity analysis and probabilistic sensitivity analysis confirmed the robustness of these results. CONCLUSION: Starting with tofacitinib and incorporating it into a csDMARDs treatment sequence is cost-effective compared to continuing csDMARDs alone in patients with RA.

Effects of Short-Term Corticosteroid Use on Reactogenicity and Immunogenicity of the First Dose of ChAdOx1 nCoV-19 Vaccine.

The effects of corticosteroid use on the reactogenicity and immunogenicity of ChAdOx1 nCoV-19 (ChAd) vaccine were evaluated. Healthcare workers (HCWs) who took low-dose corticosteroid agents around the time of the first dose of ChAd (ChAdPd group) were recruited and the reactogenicity and immunogenicity were compared with those of ChAd (ChAd group) and BNT162b2 vaccination (BNT group) of HCWs without corticosteroid exposure. The immunogenicity was measured three weeks after vaccination using quantitative anti-SARS-CoV-2 spike protein (S) antibody electrochemiluminescence immunoassay and interferon gamma (IFN-γ) release assay. A total of 67 HCWs comprising 24 ChAd, 29 BNT, and 14 ChAdPd was included. The median total corticosteroid dose of the ChAdPd group was 30 mg prednisolone equivalents (interquartile range (IQR) 20-71.3 mg). HCWs in the ChAdPd group experienced significantly milder reactogenicity (median total score 7.5, IQR 4.0-18.0) compared to those in the ChAd group (median 23.0, IQR 8.0-43.0, P=0.012) but similar to that in the BNT group (median 5.0, IQR 3.0-9.0, P=0.067). The S antibody concentration of the ChAdPd group (62.4 ± 70.0 U/mL) was higher than that of the ChAd group, though without statistical significance (3.45 ± 57.6 U/mL, P=0.192). The cellular immune response was most robust in the ChAdPd group, with significantly higher IFN-γ concentration (5.363 ± 4.276 IU/mL), compared to the ChAd (0.978 ± 1.181 IU/mL, P=0.002) and BNT (1.656 ± 1.925 IU/mL, P=0.009) groups. This finding suggest that short-term corticosteroid reduces reactogenicity of the first dose of ChAd without hindering immunogenicity.

CD8+ T Cells Require ITK-Mediated TCR Signaling for Migration to the Intestine.

The Tec kinase IL-2-inducible T cell kinase (ITK) regulates the expression of TCR-induced genes. Itk-/- T cell responses are impaired but not absent. ITK inhibition prevented colitis disease progression and impaired T cell migration to the colon in mice. To examine the function of ITK in T cell migration to the intestine, we examined the number of gut T cells in Itk-/- mice and then evaluated their expression of gut-homing receptors. Combined with in vitro murine T cell stimulation and in vivo migration assay using congenic B6 mice, we demonstrated an essential role for ITK in T cell migration to the intestine in mice. Reconstitution of Itk-/- mouse CD8+ T cells with IFN regulatory factor 4 restored gut-homing properties, providing mechanistic insight into the function of ITK-mediated signaling in CD8+ T cell migration to the intestinal mucosa in mice.

Estimation of Health Utilities Based on the Response to Treatment in Atopic Dermatitis: a Population-based Study.

PURPOSE: This study estimated utility weights based on the response to treatment for atopic dermatitis in the general population. METHODS: The Korean general population aged 20-60 years was stratified by using a random sampling method based on age and sex. Two hypothetical health states of atopic dermatitis were developed: response to treatment and no response to treatment. Health utility values were estimated by using time trade-off (TTO) based on a period of 10 years, TTO based on life expectancy, and EuroQol 5-Dimension (EQ-5D) including a visual analog scale (VAS). The mean utility value and 95% CI were derived, and comparisons of subgroups using the t test and ANOVA were performed. We conducted a multilevel analysis after controlling the sociodemographic variables to consider repeated measures. FINDINGS: A total of 155 participants were included in the survey. Their mean age was 39.7 years; 58.7% of participants were women. The mean health utility values for response and no response using TTO based on 10 years were 0.847 and 0.380, respectively. The estimated health utility values of response and no response were 0.865 and 0.476 using TTO based on life expectancy, and 0.814 and 0.279 using EQ-5D. For VAS, the response and no response were 0.744 and 0.322. After controlling the covariates, the important factors that affected utility values were response and no response to treatment (P < 0.001). IMPLICATIONS: This study showed that the utility weights of people with no response to atopic dermatitis treatment were lower compared with response from the general population. Health care providers should therefore consider symptom control as an important factor affecting the quality of life of those with atopic dermatitis.

Temperature-dependent studies on the total phenolics, flavonoids, antioxidant activities, and sugar content in six onion varieties.

Heating effect on total phenol, flavonoids, antioxidant activity, and sugar content of six onion varieties has been quantitatively investigated to explore the effect of different temperatures. The onion varieties comprised one red-skinned variety, two white-skinned varieties, and three yellow-skinned varieties. The heating temperature was scanned at 80°C, 100°C, 120°C, and 150°C for 30 minutes each, and quantitative analysis was performed relative to the powdered onion at ambient temperature. Quercetin, glucosides and sugar content were analyzed using high-performance liquid chromatography. The total phenolic and antioxidant content increased in all six varieties. The total flavonoid levels showed a considerable change. On heating the onion samples at 120°C for 30 minutes, the red-skinned variety showed the highest level of total phenolic content [13712.67 ± 1034.85 µg of gallic acid equivalent/g dry weight (µg GAE/g DW)] and total flavonoids [3456.00 ± 185.82 µg of quercetin equivalents/g dry weight (µg Q/g DW)], whereas the content of total phenolics and total flavonoids were 13611.83 ± 341.61 µg GAE/g DW and 3482.87 ± 117.17 µg Q/g DW, respectively, for the yellow-skinned (Sunpower) variety. Quercetin and its glucoside contents increased up to 120°C and then decreased at 150°C, whereas the sugar content continuously decreased with heating. All cultivars showed the same pattern in the heating effect, and the predominant flavonoids were destroyed at higher temperatures. Therefore, it is improper to expose onion powder to a temperature higher than 120°C.