Geniposide ameliorates psoriatic skin inflammation by inhibiting the TLR4/MyD88/NF-κB p65 signaling pathway and MMP9.

Psoriasis is an incurable immune-mediated disease affecting the skin or the joints. There are continuing studies on drugs for psoriasis prevention and treatment. This research found that Geniposide (GE) significantly thinned IMQ mice's skin lesions, reduced the scales, and lowered the presence of inflammatory cells in the pathology in a dose-dependent manner. GE inhibited IL-23, IL-22, IL-17A, IL-12, IL-6, and TNF-α levels in psoriatic mice serum. AKT1, TNF, TLR4, MMP9, MAPK3, and EGFR were selected as the top 6 targets of GE against psoriasis via network pharmacology, and GE-TLR4 has the most robust docking score value by molecular docking. Taken together, GE significantly inhibited TLR4 and MMP9 protein expression and influenced MyD88/NF-κB p65 signaling pathway. Finally, TLR4 was verified as the critical target of GE, which engaged in immunomodulatory activities and reduced MMP9 production in LPS and TAK-242-induced HaCaT cells. GE had a medium affinity for TLR4, and the KD value was 1.06 × 10-5 M. GE is an effective treatment and preventative strategy for psoriasis since it impacts TLR4.

Real-World Maintenance Phase Persistence on Ustekinumab and Adalimumab in Ulcerative Colitis.

Purpose: To describe real-world persistence in bio-naïve and bio-experienced adults with ulcerative colitis (UC) treated with ustekinumab, a recently approved anti-interleukin 12/23 antibody, or adalimumab, an anti-TNF biologic. Methods: This is a descriptive, retrospective cohort study. Patients initiating ustekinumab or adalimumab (index date, between 10/21/2019 and 08/13/2021) were selected from the Komodo Health comprehensive dataset and stratified into bio-naïve and bio-experienced subgroups based on biologic use 12 months pre-index date. Endpoints evaluated at 12-months after maintenance phase start using Kaplan-Meier analysis included 1) persistence; 2) persistence while being corticosteroid-free (<14 consecutive days of corticosteroid supply after day 90 post-index); and, 3) persistence while on monotherapy (no immunomodulators/non-index biologics/advanced therapies). Results: Ustekinumab cohort included 778 patients (236 bio-naïve, 542 bio-experienced) and adalimumab cohort included 1693 patients (1517 bio-naive, 176 bio-experienced). At 12 months after maintenance phase start, 75.5% and 50.5% of bio-naïve patients persisted on ustekinumab and adalimumab and 72.3% and 56.9% of bio-experienced patients persisted on ustekinumab and adalimumab, respectively. Further, 55.1% and 38.2% of bio-naïve patients were persistent and corticosteroid-free with ustekinumab and adalimumab; 43.7% and 33.4% of bio-experienced patients were persistent and corticosteroid-free with ustekinumab and adalimumab, respectively. Moreover, 68.1% and 44.5% of bio-naïve patients were persistent and on monotherapy with ustekinumab and adalimumab; 61.6% and 47.9% of bio-experienced patients were persistent and on monotherapy with ustekinumab and adalimumab, respectively. Conclusion: At 12 months after maintenance phase start, patients with UC treated with ustekinumab had numerically higher persistence, including persistence while corticosteroid-free and persistence while on monotherapy, than patients treated with adalimumab.

Ultrasound-Assisted Extraction of Atractylodes chinensis (DC.) Koidz. Polysaccharides and the Synergistic Antigastric Cancer Effect in Combination with Oxaliplatin.

Oxaliplatin (OXA) is recognized as a first-line drug for gastric cancer. However, low accumulation of the OXA in the target site and the development of drug resistance directly led to treatment failure. In the present study, an ultrasonic extraction method for Atractylodes chinensis (DC.) Koidz. polysaccharides (AKUs) and the combination treatment with OXA in vitro were studied. Results showed that when the pH level was 11, the ultrasound power at 450 W, the solid-liquid ratio was 1:20, and the ultrasound treatment for 30 min, the yield of AKUs was significantly increased to 13.20 ± 0.35%. The molecular weights of the AKUs ranged from 7.21 to 185.94 kDa, and its monosaccharides were mainly composed of arabinose (Ara), galactose (Gal), and glucose (Glu) with a ratio of 58.36, 16.90, and 15.49%, respectively. Cell experiments showed that, compared to OXA alone (2 µg/mL, inhibition rate of 18%), the treatment of OXA with AKUs had a significant synergistic inhibitory effect on MKN45 proliferation, which increased to 33, 41, and 45% with increasing AKUs concentrations (5-50 µg/mL), respectively, representing a 2.5-fold inhibition. Inductively coupled plasma-mass spectrometry (ICP-MS) determination confirmed that AKUs significantly increased the intracellular uptake of OXA by 29%, compared to that of OXA alone. We first demonstrated that the combined synergistic inhibitory effect of AKUs and OXA on gastric cancer cells was mediated by reducing the expression of efflux proteins (MRP1 and MRP2) and increasing the expression of ingested protein (OCT2). As a result of the above, AKUs deserved to be an effective adjuvant combined with chemotherapeutics in a clinical setting.

A novel pectin polysaccharide from vinegar-baked Radix Bupleuri absorbed by microfold cells in the form of nanoparticles.

Polysaccharides of vinegar-baked Radix Bupleuri (VBCP) have been reported to exhibit liver-targeting and immunomodulatory activities through oral administration, but the absorption behavior and mechanism of VBCPs have not been extensively studied. In this study, a novel HG type pectin polysaccharide, VBCP1-4, with a high molecular weight of 2.94 × 106 Da, was separated from VBCP. VBCP1-4 backbone was contained 1,4-α-D-GalpA, 1,4-α-D-GalpA6OMe, 1,3,4-α-D-GalpA and 1,2,4-α-D-Rhap. The branches were mainly contained 1,5-α-L-Araf, 1,3,5-α-L-Araf, t-α-L-Araf and t-α-D-Galp, which linked to the 3 position of 1,3,4-α-D-GalpA and the 4 position of 1,2,4-α-D-Rhap. VBCP1-4 could self-assemble to nanoparticles in water, with CMC values of 106.41 µg/mL, particle sizes of 178.20 ± 2.82 nm and zeta potentials of -23.19 ± 1.44 mV. The pharmacokinetic study of VBCP1-4, which detected by marking with FITC, revealed that it could be partially absorbed into the body through Peyer's patches of the ileum. In vitro absorption study demonstrated that VBCP1-4 was difficult to be absorbed by Caco-2 cell monolayer, but could be absorbed by M cells in a time and concentration dependent manner. The absorption mechanism was elucidated that VBCP1-4 entered M cells through clathrin-mediated endocytosis in the form of nanoparticles. These findings provide valuable insights into the absorption behavior of VBCP and contribute to its further development.

Anti-psoriasis molecular targets and active components discovery of Optimized Yinxieling Formula via affinity-purified strategy.

Psoriasis, a prevalent inherited skin condition, involves an inflammatory response as a key pathogenic mechanism. The Optimized Yinxieling Formula (OYF), rooted in traditional Chinese medicine, is extensively utilized in clinical settings to treat psoriasis. Although previous studies have demonstrated OYF's significant anti-inflammatory effects in psoriasis, its potential molecular targets and active components remain unexplored. This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF. Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators, including IL-23, nitric oxide, TNF-α, and IL-1ß, in LPS-induced RAW264.7 cells. We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy, known as Target Fishing. The enriched target proteins were subsequently identified via LC-MS/MS, followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network. We identified a total of 76 potential target proteins, which were highly associated with mRNA transcription mechanisms. In particular, pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract. We further utilized a target protein-based affinity capture strategy, combined with LC-MS and SPR analysis, to globally screen OYF's active components, focusing on the mRNA transcription regulator, fused in sarcoma (FUS). This process led to the identification of umbelliferone, vanillic acid, protocatechuic acid, gentisic acid, and echinacoside as key compounds targeting FUS to inhibit IL-23 expression. Additionally, we formulated a compound cocktail (CpdC), which significantly reduced psoriasis area and severity index (PASI) scores and the expressions of IL-23 and Ki67 in an imiquimod (IMQ)-induced psoriasis mouse model. Collectively, our study elucidates the primary molecular targets and active components of OYF, offering novel insights for psoriasis treatment.

Xiaoyaosan promotes neurotransmitter transmission and alleviates CUMS-induced depression by regulating the expression of Oct1 and Oct3 in astrocytes of the prefrontal cortex.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyaosan (XYS) is a traditional prescription for the treatment of liver depression and qi stagnation, and pharmacological studies have shown that XYS has great potential to reverse depression. However, anti-depression targets and the mechanism of XYS are still not entirely clear. AIM OF THE STUDY: The present study aims to explore and verify the anti-depression mechanism of XYS. MATERIALS AND METHODS: The antidepressant effect of XYS was assessed in rats with depression induced by chronic unpredictable mild stimulation (CUMS). The levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in different brain regions were measured using ELISA. The expression of organic cation transporters (Octs) were detected by western blot and immunohistochemical techniques. Then, Decynium-22 (D22), an Octs inhibitor, was injected into the prefrontal cortex (PFC) to verify the correlation between Octs and depression-like behavior. Then, the effects of XYS on the behavior, neurotransmitter concentration, and Octs expression in D22-induced rats were examined. Finally, primary astrocytes were used to verify the mechanism of XYS exerting anti-depressant activity by regulating Octs. RESULTS: The result showed that XYS had a significant positive impact on the behavior of depression rats induced by CUMS. XYS also improved the secretion of 5-HT, DA, and NE in the PFC, as well as the promotion of Oct1, Oct2, and Oct3 expression in the PFC. These results suggest that XYS has the potential to alleviate depression by enhancing the secretion of neurotransmitters. This may be related to XYS regulation of Oct's expression. When the expression of Octs was inhibited in the PFC, rats exhibited behavior similar to depression, and XYS was able to reverse this behavior, indicating that Octs play a significant role in the development of depression and XYS may exert its antidepressant effects through the regulation of Octs. Furthermore, the study also found that dopamine uptake decreased after inhibiting the expression of Octs, and XYS-containing serum could reverse the downregulation of Oct1 and Oct3 and promote intracellular dopamine homeostasis in the astrocytes. Overall, XYS may exert antidepressant effects by promoting dopamine uptake to improve neurotransmitter transport by regulating the protein expression of Oct1 and Oct3 in astrocytes. CONCLUSIONS: The antidepressant effect of XYS may be attributed to its ability to regulate the expression of Oct1 and Oct3 in astrocytes of the PFC, thereby promoting neurotransmitter transport.

Burden of chronic corticosteroid use among patients with ulcerative colitis initiated on targeted treatment or conventional therapy in the United States.

BACKGROUND: Chronic corticosteroid use is common in ulcerative colitis (UC); however, real-world evidence of its burden to the health care system is limited. OBJECTIVE: To quantify chronic corticosteroid use burden in UC. METHODS: Adults with UC initiated on targeted treatments (ie, biologics and advanced/small molecule therapies) or conventional therapy (index date) were selected from a deidentified US insurance claims database (January 1, 2004, to September 30, 2021). Targeted treatments and conventional therapy initiators were stratified into chronic (>90 days corticosteroid use 12 months post-index [landmark]) and nonchronic corticosteroid users. Patient characteristics 12 months pre-index were balanced with inverse probability of treatment weighting. Health care resource use, costs (US$ 2021), and corticosteroid-related complications were compared in the 12 months post-landmark. RESULTS: Targeted treatment initiators included 1,886 chronic and 1,911 nonchronic corticosteroid users; conventional therapy initiators included 4,980 chronic and 5,199 nonchronic users. Chronic vs nonchronic users had 94% more inpatient days and 16% more outpatient visits among targeted treatment initiators, and 135% more inpatient days and 30% more outpatient visits among conventional therapy initiators (all P < 0.01). Mean all-cause total costs per patient per year were $73,491 for chronic vs $58,884 for nonchronic users ($14,607 higher; P < 0.01) for targeted treatment initiators, and $39,335 for chronic vs $21,271 for nonchronic users ($18,065 higher; P < 0.01) for conventional therapy initiators. Odds of infection and bone loss were 14% and 113% higher, respectively, in chronic vs nonchronic users among targeted treatment initiators and 29% and 47% higher in chronic vs nonchronic users among conventional therapy initiators (all P < .01). CONCLUSIONS: The results of this study suggest that chronic corticosteroid use is associated with substantial clinical and economic burden and may indicate unmet needs in the management of UC progression.

Improvements in Patient-Reported Outcomes Through Six Months of Guselkumab Treatment in Patients With Active Psoriatic Arthritis: Real-World Data From the CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry.

OBJECTIVE: Evaluate patient-reported outcomes after 6 months of on-label guselkumab use in patients with rheumatologist-diagnosed active psoriatic arthritis (PsA) enrolled in the CorEvitas PsA/Spondyloarthritis Registry. METHODS: This analysis includes registry participants who initiated and persisted with on-label guselkumab (after US Food and Drug Administration approval for PsA; 100 mg at weeks 0, 4, and every 8 weeks) at their 6-month follow-up visit (On-Label Persisters). Among patients not meeting response criteria at baseline, responses at 6 months were determined for patient-reported outcomes, including patient-reported pain (0-100 mm visual analog scale), patient global assessment of arthritis + psoriasis (PtGA; 0-100 visual analog scale), and Health Assessment Questionnaire-Disability Index (HAQ-DI; 0-3). Unadjusted, nominal P values were calculated via single-proportion, one-sided test (H0 = 0%; α = 0.05). RESULTS: Of 90 On-Label Persisters, most had treatment-resistant PsA (92.2% and 73.3% previously received ≥1 and ≥2 biologic/targeted synthetic disease-modifying antirheumatic drugs, respectively), with mean (SD) baseline patient-reported pain, PtGA, and HAQ-DI scores of 57.0 (24.6), 50.3 (24.4), and 0.9 (0.6), respectively. Among those with patient-reported pain and PtGA scores of at least 15 at baseline, 40.2% (33/82) and 46.8% (36/77), respectively, achieved at least 15-mm reductions at 6 months; among those with HAQ-DI scores of at least 0.35 and more than 0.5 at baseline, respectively, 30.4% (21/69) achieved improvements of at least 0.35 and 10.3% (6/58) achieved scores of 0.5 or lower at 6 months (all nominal P < 0.001). CONCLUSION: Pain and physical function are important contributors to health-related quality of life. In this real-world population of patients with treatment-resistant PsA and 6 months of persistent guselkumab treatment, clinically meaningful improvements in pain and physical function were achieved by approximately 40% and 30% of patients, respectively.

Hypofractionated radiotherapy for refractory or relapsed aggressive B-cell lymphoma in the rituximab era.

BACKGROUND: Radiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of hypofractionated RT in this setting has not been confirmed. METHODS: We retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed. RESULTS: A total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3-5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2-27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-of-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-of-field relapses. PFS was associated with response to RT (P = 0.001) and numbers of residual sites (P < 0.001). No serious non-hematological adverse effects (≥ grade 3) associated with RT were reported. CONCLUSION: These data suggest that hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

Economic and clinical burden of chronic corticosteroid use in patients with Crohn[apos]s disease initiated on biologic or conventional therapies in the US: A retrospective claims study.

BACKGROUND: Chronic corticosteroid (CS) use is associated with complications, but estimates of the economic and clinical burden in patients with Crohn's disease (CD) are lacking. OBJECTIVE: To estimate the burden of chronic CS use in CD in the United States in terms of health care resource utilization (HRU), health care costs, and CS-related complications. METHODS: This was a retrospective study of adults with CD initiated on biologics or conventional therapies (index date). Patients from a deidentified insurance claims database (2004-2021) were classified as chronic CS users (>90 days of CS use) or nonchronic CS users based on a 12-month landmark period starting on the index date. Patient baseline characteristics were balanced, and outcomes (HRU, costs [2021 US dollars], and CS-related complications) 12 months after the landmark period were compared between CS groups using regressions with nonparametric bootstrap resampling to estimate confidence intervals and P values. RESULTS: Biologic initiators (mean age: 44 years, 55% female) included 3366 chronic and 3401 nonchronic CS users; conventional therapy initiators (mean age: 51 years, 59% female) included 3657 chronic and 3727 nonchronic CS users. Compared with nonchronic users, chronic users had significantly more inpatient days and outpatient visits (biologic initiators: 37% and 24% more, respectively; conventional therapy initiators: 36% and 17%, respectively; all P<0.05). Chronic users also had significantly higher mean all-cause total costs per-patient-per year (biologic: $72,967 vs. $63,100, mean cost difference [MCD] = $9867; conventional therapy: $40,144 vs. $26,426, MCD = $13,718; all P<0.001), as well as higher odds of infection (biologic: 14% higher; conventional therapy: 20% higher) and bone loss (63% and 41%, respectively) (all P<0.05). CONCLUSION: Chronic CS use in patients with CD is associated with a significant economic and clinical burden including higher HRU, health care costs, and prevalence of complications, suggesting unmet needs in the clinical management of this population.

Dual-crosslinking immunostimulatory hydrogel synchronously suppresses pancreatic fistula and pancreatic cancer relapse post-resection.

In pancreatic cancer (PC), surgical resection remains the sole curative option, albeit patients undergoing resection are susceptible to postoperative pancreatic fistula (PF) formation and tumor recurrence. An unmet need exists for a unified strategy capable of concomitantly averting PF and tumor relapse to mitigate morbidity in PC patients after surgery. Herein, an original dual crosslinked biological sealant hydrogel (methacrylate-hyaluronic acid-dopamine (MA-HA-DA) and sulfhydryl-hyaluronic acid-dopamine (SH-HA-DA)) was engineered as a drug depot and loaded with polydopamine-cloaked cytokine interleukin-15 and platelets conjugated with anti-TIGIT. In vitro analyses validated favorable tissue adhesion, cytocompatibility, and stability of the hydrogels. In a PF rodent model, the hydrogel effectively adhered to the pancreatic stump, sealing the severed pancreatic end and impeding post-operative elevations in amylase and lipase. In PC murine models, hydrogels potently stimulated CD8+ T and NK cells to deter residual tumor re-growth and distant metastasis. This innovative hydrogel strategy establishes a new framework for concomitant prevention of PF and PC recurrence.

Evaluation of Treatment Patterns and Maintenance Dose Titration Among Patients With Crohn's Disease Initiating Biologics With 3 Years of Follow-Up.

Background: There is limited real-world evidence on treatment patterns of patients with Crohn's disease (CD) initiating biologics with an extensive follow-up period. This study describes persistence and dose titration among CD patients with 3 years of follow-up. Methods: This retrospective observational study was conducted using the STATinMED RWD Insights all-payer medical and pharmacy data. Adult patients with at least 1 CD medical claim and at least 1 medical/pharmacy claim for a biologic (adalimumab [ADA], certolizumab pegol (CZP), infliximab [IFX] and its biosimilar products [IFX-BS], ustekinumab [UST], and vedolizumab [VDZ]) between September 2016 and October 2018 were identified. Commercially insured patients with continuous capture for at least 12 months before and at least 36 months after biologics initiation were selected. Confirmed CD patients were included in the final cohort. Baseline patient characteristics and treatment patterns over the 3-year follow-up period were evaluated. Results were summarized using means and SD or counts and percentages. Results: A total of 2309 confirmed patients with CD were identified (847 [36.7%] IFX, 534 [23.1%] ADA, 486 [21.1%] VDZ, 394 [17.1%] UST, 85 [3.7%] CZP, and 72 [3.1%] IFX-BS). CZP and IFX-BS were excluded due to small sample sizes. Approximately half of CD patients were between ages 35 and 54. Patients on UST had a higher Charlson Comorbidity Index score. Common comorbidities (>10%) included anemia, anxiety, depression, and hypertension. Persistence over 3 years' follow-up was highest for UST (61.4%) patients, followed by VDZ (58.0% ), ADA (52.1% , and IFX (48.1%). The discontinuation rate without switch or restart was highest for ADA (37.3%), followed by UST (30.7%), IFX (28.1%), and VDZ (25.3%). Over the 3 years of follow-up, the dose titration rate was highest for IFX (76.5%) and lowest for UST (50.8%). In particular, UST had the lowest dose escalation rate (35.5%) and highest dose-reduction rate (16.5%). Conclusions: Patients with CD on UST had the highest persistence and lowest dose escalation across different biologic users over the 3-year follow-up period, possibly suggesting a better clinical response of UST. Future studies with longer follow-up adjusting for confounders are needed to better understand treatment patterns among biologics users.

Persistence and Dose Escalation During Maintenance Phase and Use of Nonbiologic Medications Among Patients With Ulcerative Colitis Initiated on Ustekinumab in the United States.

Background: Real-world data on treatment patterns among patients with ulcerative colitis (UC) initiated on ustekinumab are limited. Methods: Adults with UC initiated on ustekinumab (index date) between 10/18/2019 and 04/31/2022 were selected from a deidentified health insurance claims database (Symphony Health, an ICON plc Company, PatientSource). Persistence (no gaps in days of supply >120 days), persistence while being corticosteroid-free (no corticosteroid use for ≥14 days of supply after a 90-day grace period from index date) and dose escalation (≥2 consecutive subcutaneous claims ≥100% above daily maintenance dose) were described during the maintenance phase using Kaplan-Meier analysis. Nonbiologic treatments, among patients with ≥2 ustekinumab claims within 90 days post-index and ≥6 months of follow-up, were compared with logistic models 6 months post- versus pre-ustekinumab initiation. Results: 6565 patients on ustekinumab entered the maintenance phase. At month 12 of the maintenance phase, 72.0% (95% confidence interval [CI]: 70.1%-73.9%) were persistent, 50.8% (95% CI: 48.7%-52.9%) were persistent and corticosteroid-free, and 19.2% (95% CI: 17.3%-21.3%) of patients had dose escalation. In the 6 months post- versus pre-ustekinumab initiation, the odds of nonbiologic medication use assessed in 4147 patients were significantly lower: 57% lower odds for corticosteroid, 46% for 60 cumulative days of corticosteroid, 42% for 5-aminosalicylic acid, and 24% for immunomodulators (all P < .001). Conclusions: Most patients with UC reaching the maintenance phase on ustekinumab remained persistent after 12 months of maintenance therapy. Nonbiologic medication use post-ustekinumab initiation was significantly lower, notably for corticosteroids. Given the multiple complications associated with chronic corticosteroid use, this reduction can be seen as clinically relevant and informs treatment choice for patients with UC.

Long-term persistence and other treatment patterns among bio-naïve patients with Crohn's disease treated with ustekinumab or adalimumab.

OBJECTIVE: To estimate long-term persistence among bio-naïve patients with CD initiated on ustekinumab or adalimumab. METHODS: Adults with CD initiating ustekinumab or adalimumab (index date, between September 23, 2016 and August 1, 2019) were sampled from the IBM MarketScan Commercial Database. Patients without CD-indicated biologics (bio-naïve) and with no diagnoses for other autoimmune diseases 12 months pre-index date (baseline) were included. Cohorts were balanced on baseline characteristics with inverse probability of treatment weighting. Persistence was defined as the absence of therapy exposure gaps >120 days (ustekinumab) or >60 (adalimumab) between days of supply. Composite endpoints were persistence and being corticosteroid-free (no corticosteroids >14 days of supply after day 90 post-index) and persistence while on monotherapy (no immunomodulators/non-index biologics). Persistence was analyzed using Kaplan-Meier and Cox's models. RESULTS: Ustekinumab and adalimumab cohorts included 671 and 2,975 patients. At 12 months post-index, ustekinumab patients were significantly more persistent (hazard ratio [HR] = 1.60; 95% confidence interval [CI] = 1.33-1.93), persistent while on monotherapy (HR = 1.43; 95% CI = 1.24-1.65), and trended toward being more persistent and corticosteroid-free (HR = 1.14; 95% CI = 0.99-1.30) vs adalimumab. At 24 months post-index, ustekinumab patients were significantly more persistent (HR = 1.66; 95% CI = 1.40-1.97), persistent while on monotherapy (HR = 1.44; 95% CI = 1.26-1.64), and persistent and corticosteroid-free (HR = 1.15; 95% CI = 1.01-1.31) vs adalimumab. CONCLUSIONS: Bio-naïve patients with CD initiated on ustekinumab demonstrated significantly more persistence than patients initiated on adalimumab at 12 and 24 months of treatment. Long-term persistence is a measure of a drug's real-world performance and findings may aid clinical decision-making.

Choosing a treatment on which a patient can stay over a long period of time is key for the successful management of chronic conditions such as Crohn's disease. Information on whether and how long patients stay on treatment can help physicians make the right therapeutic choice. This study examined whether adults with Crohn's disease, who have not previously taken biologics, stay on treatment longer when given the biologic ustekinumab or adalimumab. At 12 and 24 months after starting the treatment, a larger proportion of patients were still using ustekinumab compared with adalimumab. The proportion of patients using the biologic without immunomodulators or other biologics was also higher with ustekinumab. The results suggest that patients without previous biologic experience stay on treatment longer with ustekinumab than with adalimumab.

Comparative Study on Anti-Inflammatory Effect of Polysaccharides from Vinegar-Baked Radix Bupleuri Using Different Methods.

The impact of the extraction method on the physiochemical characteristics and anti-inflammatory effect of polysaccharides from vinegar-baked Radix Bupleuri (VBCPs) was studied. Five extraction methods were employed to obtain the VBCPs: hot water extraction (HW), ultrasound-assisted extraction (UA), enzyme-assisted extraction (EA), citric acid-assisted extraction (CA), and ammonia-assisted extraction (KA). The results showed that the extraction method affects the yield, characteristics, and anti-inflammatory effect of the polysaccharides significantly. KA produced the highest yield, Ara content, and the strongest effect of enhancing IL-10 secretion. VBCP-EA exhibited the largest molecular weight (Mw), the highest Man content, and the poorest effect on inhibiting NO, VBCP-UA possessed more Gal than other VBCPs, the lowest Mw, and a comparable effect on inhibiting NO and TNF-α with VBCP-KA and VBCP-CA. All VBCP self-assembled into nanoparticles in solutions, and VBCP-KA presented the lowest particle size. The structure-activity analysis showed that Mw and Man content are negatively correlated and Ara content is positively correlated with the NO inhibition and IL-10 secretion effects; Rha and Gal A content are positively correlated and Glu is negatively correlated with the TNF-α inhibiting effect. The above results indicated that KA is an efficient method for obtaining anti-inflammatory VBCP, which provides new insight into the extraction of VBCP.

Persistence and other treatment patterns among bio-experienced patients with Crohn's disease initiated on ustekinumab or adalimumab.

BACKGROUND: Real-world data on persistence on ustekinumab and adalimumab among bio-experienced patients with Crohn's disease (CD) are limited. OBJECTIVE: To compare treatment persistence and describe switching, restart, and dose titration among bio-experienced patients with CD initiated on ustekinumab or adalimumab. METHODS: IBM MarketScan Commercial Database was used to identify bio-experienced adults with CD who were assigned to either the ustekinumab or adalimumab cohort based on the agent first initiated (index date) after September 23, 2016. Cohorts were balanced using inverse probability of treatment weights-average treatment effect on treated. Persistence on index agent (absence of exposure gap > 120 days for ustekinumab or > 60 days for adalimumab), persistence while corticosteroid-free, and persistence while receiving monotherapy were assessed at 12 months after index date and compared between cohorts using weighted Kaplan-Meier and Cox proportional hazards model analyses. RESULTS: Among 903 patients in the ustekinumab cohort and 525 patients in the adalimumab cohort, baseline characteristics were balanced after weighting. At 12 months post-index, ustekinumab was associated with higher persistence (80.1% vs 64.6%; hazard ratio = 2.02 [95% CI = 1.60-2.56]; P < 0.001) and persistence while receiving monotherapy (51.6% vs 40.0%; 1.51 [1.28-1.78]; P < 0.001) vs adalimumab. Persistence while corticosteroid-free was similar in the ustekinumab vs adalimumab cohort (50.1% vs 48.2%; 1.19 [1.00-1.41]; P = 0.0516). CONCLUSIONS: This retrospective real-world study demonstrated that among bio-experienced patients with CD, initiation of ustekinumab was associated with better persistence at 12 months of follow-up, including persistence while receiving monotherapy, compared with adalimumab. DISCLOSURES: This study was funded by Janssen Scientific Affairs, LLC. Drs Zhao, Ding, and Kachroo are employees of Janssen Scientific Affairs, LLC, and stockholders of Johnson & Johnson. Dr Manceur, Mr Lefebvre, Ms Zhdanava, and Mr Pilon are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC, which funded the development and conduct of this study and article. Mr Holiday was an employee of Analysis Group, Inc., at the time of study conduct.

Persistence Among Patients with Crohn Disease Previously Treated with an Anti-tumor Necrosis Factor Inhibitor and Switching or Cycling to Another Biologic Agent.

PURPOSE: Nonresponse to an anti-tumor necrosis factor (TNF) agent in patients with Crohn disease (CD) is often managed by either a switch to a different class of biologic (ie, ustekinumab, vedolizumab) or by cycling to another anti-TNF agent (ie, adalimumab, infliximab, certolizumab pegol). Persistence after a switch to a different biologic class or after cycling within the anti-TNF class was assessed in patients with nonresponse to an anti-TNF agent. METHODS: Adults with CD who discontinued from an anti-TNF agent and either switched to a different class of biologic (ie, anti-interleukin/integrin; the switching cohort) or cycled within the anti-TNF class (the cycling cohort) between September 23, 2016, and August 1, 2019, were selected from a commercial database. The index date was defined as the date of the first claim of the subsequent-line biologic (index biologic) after an anti-TNF. The switching and cycling cohorts were balanced with regard to baseline characteristics, using inverse probability of treatment weights-average treatment effect (IPTW-ATE). Persistence with the index biologic was defined as consistent use with no gaps of >120 days (ustekinumab, vedolizumab, infliximab) or of >60 days (adalimumab, certolizumab pegol) in biologic supply. Composite end points were persistence while being corticosteroid-free (defined as no use of corticosteroids with ≥14 days of supply after day 90 post-index) and persistence while on monotherapy (no immunomodulators/nonindex biologics). Weighted Kaplan-Meier and Cox models were used to assess outcomes at 12 months post-index. FINDINGS: There were 444 patients in the weighted switching cohort (mean age, 40.4 years; 56.3% female) and 441 in the weighted cycling cohort (mean age, 39.5 years; 58.4% female). At 12 months post-index, the rate of persistence with the index biologic was 75.7% in the switching cohort compared to 67.5% in the cycling cohort (log-rank P = 0.023); the rate of persistence while on monotherapy was 58.2% compared to 44.2%, respectively (log-rank P < 0.001). The rate of persistence was 44% greater in the switching compared to that in the cycling cohort (hazard ratio [HR] = 1.44; 95% CI, 1.11-1.88; P = 0.007); the rate of persistence while on monotherapy was 56% greater in the switching cohort (HR = 1.56; 95% CI, 1.28-1.90; P < 0.001). The between-cohort difference in persistence while being corticosteroid-free was not statistically significant (HR = 1.08; 95% CI, 0.89-1.32; P = 0.426). IMPLICATIONS: Patients with CD who switched to a different biologic class were more persistent than were patients who cycled to another anti-TNF agent. These findings may be useful for physicians when considering the treatment of patients who have experienced nonresponse or loss of response to the first-line anti-TNF agent.

Low-temperature phenol-degrading microbial agent: construction and mechanism.

In this study, three cold-tolerant phenol-degrading strains, Pseudomonas veronii Ju-A1 (Ju-A1), Leifsonia naganoensis Ju-A4 (Ju-A4), and Rhodococcus qingshengii Ju-A6 (Ju-A6), were isolated. All three strains can produce cis, cis-muconic acid by ortho-cleavage of catechol at 12 â„ƒ. Response surface methodology (RSM) was used to optimize the proportional composition of low-temperature phenol-degrading microbiota. Degradation of phenol below 160 mg L-1 by low-temperature phenol-degrading microbiota followed first-order degradation kinetics. When the phenol concentration was greater than 200 mg L-1, the overall degradation trend was in accordance with the modified Gompertz model. The experiments showed that the microbial agent (three strains of low-temperature phenol-degrading bacteria were fermented separately and constructed in the optimal ratio) could completely degrade 200 mg L-1 phenol within 36 h. The above construction method is more advantageous in bio-enhanced treatment of actual wastewater. Through the construction of microbial agents to enhance the degradation effect of phenol, it provides a feasible scheme for the biodegradation of phenol wastewater at low temperature and shows good application potential.

Citric Acid Enhances the Activities of Astilbin on Psoriasis via Down-Regulation of P-Glycoprotein.

Astilbin (AS) has been confirmed to be an attractive candidate drug for psoriasis; however, the low oral absorption limits its further development and utilization. Herein, a simple method was discovered to solve this problem, which was combined with citric acid (CA). The efficiency was estimated by imiquimod (IMQ)-induced psoriasis-like mice, and the absorption was predicted by the Ussing chamber model, HEK293-P-gp cells were used to validate the target. Compared with the AS group, the combination with CA significantly reduced the PASI score and down-regulated the protein expression of IL-6 and IL-22, which showed that the combination of CA enhanced the anti-psoriasis effect of AS. Moreover, AS concentration in psoriasis-like mice plasma was significantly increased (3.90-fold) in the CA combined group, and the mRNA and protein levels of P-gp in the small intestine of the combined group were decreased by 77.95 and 30.00%, respectively. In addition, when combined with CA, AS absorption significantly increased while the efflux ratio decreased in vitro. Furthermore, CA significantly elevated the uptake of AS by 153.37% and decreased the protein expression of P-gp by 31.70% in HEK293-P-gp cells. These results indicated that CA enhanced the therapeutic efficacy of AS by improving its absorption via down-regulation of P-gp.

Determinants and Assembly Mechanism of Bacterial Community Structure in Ningxia Section of the Yellow River.

The Yellow River is a valuable resource in the Ningxia Hui Autonomous Region and plays a vital role in local human activities and biodiversity. Bacteria are a crucial component of river ecosystems, but the driving factors and assembly mechanisms of bacterial community structure in this region remain unclear. Herein, we documented the bacterial community composition, determinants, co-occurrence pattern, and assembly mechanism for surface water and sediment. In comparison to sediment, the bacterioplankton community showed significant seasonal variation, as well as less diversity and abundance. The network topology parameters indicated that the sediment bacterial network was more stable than water, but the bacterioplankton network had higher connectivity. In this lotic ecosystem, CODMn, Chl a, and pH affected the structure of the bacterioplankton community, while TP was the primary factor influencing the structure of the sediment bacterial community. The combined results of the neutral community model and the phylogenetic null model indicate that Bacterial communities in both habitats were mainly affected by stochastic processes, with ecological processes dominated by ecological drift for bacterioplankton and dispersal limitation for sediment bacteria. These results provide essential insights into future research on microbial ecology, environmental monitoring, and classified management in the Ningxia section of the Yellow River.